| 1 | Mol. Psychiatry 2002 -1 7: 673-82 |
|---|---|
| PMID | 12192610 |
| Title | Abnormal expression of epidermal growth factor and its receptor in the forebrain and serum of schizophrenic patients. |
| Abstract | Epidermal growth factor (EGF) comprises a structurally related family of proteins containing heparin-binding EGF-like growth factor (HB-EGF) and transforming growth factor alpha (TGFalpha) that regulates the development of dopaminergic neurons as well as monoamine metabolism. We assessed the contribution of EGF to schizophrenia by measuring EGF family protein levels in postmortem brains and in fresh serum of schizophrenic patients and control subjects. EGF protein levels were decreased in the prefrontal cortex and striatum of schizophrenic patients, whereas the levels of HB-EGF and TGFalpha were not significantly different in any of the regions examined. Conversely, EGF receptor expression was elevated in the prefrontal cortex. Serum EGF levels were markedly reduced in schizophrenic patients, even in young, drug-free patients. Chronic treatment of animals with the antipsychotic drug haloperidol had no influence on EGF levels in the brain or serum. These findings suggest that there is abnormal EGF production in various central and peripheral tissues of patients with both acute and chronic schizophrenia. EGF might thus provide a molecular substrate for the pathologic manifestation of the illness, although additional studies are required to determine a potential link between impaired EGF signaling and the pathology/etiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 2 | Mol. Psychiatry 2002 -1 7: 673-82 |
| PMID | 12192610 |
| Title | Abnormal expression of epidermal growth factor and its receptor in the forebrain and serum of schizophrenic patients. |
| Abstract | Epidermal growth factor (EGF) comprises a structurally related family of proteins containing heparin-binding EGF-like growth factor (HB-EGF) and transforming growth factor alpha (TGFalpha) that regulates the development of dopaminergic neurons as well as monoamine metabolism. We assessed the contribution of EGF to schizophrenia by measuring EGF family protein levels in postmortem brains and in fresh serum of schizophrenic patients and control subjects. EGF protein levels were decreased in the prefrontal cortex and striatum of schizophrenic patients, whereas the levels of HB-EGF and TGFalpha were not significantly different in any of the regions examined. Conversely, EGF receptor expression was elevated in the prefrontal cortex. Serum EGF levels were markedly reduced in schizophrenic patients, even in young, drug-free patients. Chronic treatment of animals with the antipsychotic drug haloperidol had no influence on EGF levels in the brain or serum. These findings suggest that there is abnormal EGF production in various central and peripheral tissues of patients with both acute and chronic schizophrenia. EGF might thus provide a molecular substrate for the pathologic manifestation of the illness, although additional studies are required to determine a potential link between impaired EGF signaling and the pathology/etiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 3 | Nippon Rinsho 2003 Mar 61: 521-8 |
| PMID | 12701184 |
| Title | [Contribution of neurotrophic factors and cytokines to schizophrenia]. |
| Abstract | Abnormal development of the brain is implicated in the etiology and/or pathology of various psychiatric diseases, including schizophrenia. Current evidence indicates that neurotrophic factors can strongly influence neuronal phenotypic differentiation and subsequent neuronal function in synaptic plasticity. Among various neurotrophic factors, the expression of brain-derived neurotrophic factor(BDNF) and epidermal growth factor (EGF) is impaired in the brain as well as in the periphery of patients with schizophrenia. Based on this result, a novel animal model for schizophrenia has been established by perturbing the neurotrophic signaling during development. This review summarizes the latest progress of these studies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 4 | Exp. Cell Res. 2003 Mar 284: 14-30 |
| PMID | 12648463 |
| Title | Neuregulins: functions, forms, and signaling strategies. |
| Abstract | The neuregulins (NRGs) are cell-cell signaling proteins that are ligands for receptor tyrosine kinases of the ErbB family. The neuregulin family of genes has four members: NRG1, NRG2, NRG3, and NRG4. Relatively little is known about the biological functions of the NRG2, 3, and 4 proteins, and they are considered in this review only briefly. The NRG1 proteins play essential roles in the nervous system, heart, and breast. There is also evidence for involvement of NRG signaling in the development and function of several other organ systems, and in human disease, including the pathogenesis of schizophrenia and breast cancer. There are many NRG1 isoforms, raising the question "Why so many neuregulins?" Study of mice with targeted mutations ("knockout mice") has demonstrated that isoforms differing in their N-terminal region or in their epidermal growth factor (EGF)-like domain differ in their in vivo functions. These differences in function might arise because of differences in expression pattern or might reflect differences in intrinsic biological characteristics. While differences in expression pattern certainly contribute to the observed differences in in vivo functions, there are also marked differences in intrinsic characteristics that may tailor isoforms for specific signaling requirements, a theme that will be emphasized in this review. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 5 | Invest. Ophthalmol. Vis. Sci. 2003 Sep 44: 3927-32 |
| PMID | 12939311 |
| Title | Calcium activates SK channels in the intact human lens. |
| Abstract | Apamin-sensitive, calcium-activated SK potassium channels have been implicated in schizophrenia and myotonic dystrophy (MD), and both conditions carry an increased risk of cataract. The presence and functional activity of SK channels were therefore investigated in the human lens. The expression of all three members of the SK channel family was quantified by PCR. Their functional activity was investigated by using electrophysiological and calcium-imaging techniques. Lens voltage was monitored by inserting a single electrode into the intact human lens, and changes in intracellular calcium were recorded simultaneously after fura-2 incorporation. Expression of all three SK family members was detected in both anterior and equatorial lens epithelial cells. Application of either G-protein (e.g., adenosine triphosphate [ATP]) or tyrosine kinase (EGF) receptor agonists induced a hyperpolarization of lens voltage that was accompanied by an increase in intracellular calcium. The calcium ionophore ionomycin also induced a rapid hyperpolarization. The hyperpolarizing responses were abolished by apamin and trifluoperazine and were accentuated by the SK channel activator 1-ethyl-2-benzimidazolinone (1-EBIO). SK channels are an integral part of the G-protein and tyrosine kinase calcium signaling mechanisms in the human lens, and their activation is inhibited by certain anti-psychotic drugs. These findings help explain why a change in channel activity, whether by abnormal gene expression or by drug intervention, can lead to cataract. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 6 | Mol. Psychiatry 2003 Jan 8: 19-29 |
| PMID | 12556905 |
| Title | Neonatal perturbation of neurotrophic signaling results in abnormal sensorimotor gating and social interaction in adults: implication for epidermal growth factor in cognitive development. |
| Abstract | Epidermal growth factor (EGF) and its structurally related proteins are implicated in the developmental regulation of various brain neurons, including midbrain dopaminergic neurons. There are EGF and EGF receptor abnormalities in both brain tissues and blood from schizophrenic patients. We administered EGF to neonatal rats to transiently perturb endogenous EGF receptor signaling and evaluated the neurobehavioral consequences. EGF-treatment-induced transient impairment in tyrosine hydroxylase expression. The animals grew normally, exhibited normal weight increase, glial growth, and gross brain structures, and later lost the tyrosine hydroxylase abnormality. During and after development, however, the rats began to display various behavioral abnormalities. Abnormal sensorimotor gating was apparent, as measured by deficits in prepulse inhibition of acoustic startle. Motor activity and social interaction scores of the EGF-treated animals were also impaired in adult rats, though not in earlier developmental stages. In parallel, there was a significant abnormality in dopamine metabolism in the brain stem of the adult animals. Gross learning ability appeared to be normal as measured by active avoidance. These behavioral alterations, which are often present in schizophrenic models, were ameliorated by subchronic treatment with clozapine. Although the molecular and/or physiologic background(s) of these behavioral abnormalities await further investigation, the results of the present experiment indicate that abnormal EGF receptor stimulation given during limited neonatal stages can result in severe and persistent cognitive/behavioral dysfunctions, which appear only in adulthood. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 7 | Neuroreport 2004 May 15: 1215-8 |
| PMID | 15129177 |
| Title | Association of EGF polymorphism with schizophrenia in Finnish men. |
| Abstract | Some recent data suggest that epidermal growth factor (EGF) protein levels are altered in the brain of schizophrenic patients. In addition, a novel polymorphism of the EGF gene is associated with enhanced production of EGF in vitro. We conducted a retrospective study to explore the impact of EGF polymorphism on factors associated with schizophrenia. The sample consisted of 94 patients with schizophrenia who had either responded to treatment with conventional neuroleptics or who were considered non-responders. The control sample consisted of 98 blood donors. In our sample, the G allele was associated with schizophrenia in male patients (OR = 3.594 (95% CI 1.347-9.591), p = 0.008). The G allele was also associated with a later age at onset in male patients with schizophrenia. However, no association was found between treatment response and EGF polymorphism. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 8 | Neuroreport 2004 May 15: 1215-8 |
| PMID | 15129177 |
| Title | Association of EGF polymorphism with schizophrenia in Finnish men. |
| Abstract | Some recent data suggest that epidermal growth factor (EGF) protein levels are altered in the brain of schizophrenic patients. In addition, a novel polymorphism of the EGF gene is associated with enhanced production of EGF in vitro. We conducted a retrospective study to explore the impact of EGF polymorphism on factors associated with schizophrenia. The sample consisted of 94 patients with schizophrenia who had either responded to treatment with conventional neuroleptics or who were considered non-responders. The control sample consisted of 98 blood donors. In our sample, the G allele was associated with schizophrenia in male patients (OR = 3.594 (95% CI 1.347-9.591), p = 0.008). The G allele was also associated with a later age at onset in male patients with schizophrenia. However, no association was found between treatment response and EGF polymorphism. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 9 | Ann. N. Y. Acad. Sci. 2004 Oct 1025: 612-8 |
| PMID | 15542770 |
| Title | Conditioned place preference and locomotor sensitization after repeated administration of cocaine or methamphetamine in rats treated with epidermal growth factor during the neonatal period. |
| Abstract | Epidermal growth factor (EGF) and its structurally related proteins are involved in the developmental regulation of various brain neurons, including midbrain dopaminergic neurons. We recently reported EGF and EGF-receptor abnormalities in both the brain tissues and blood of schizophrenic patients. Administration of EGF to neonatal rats transiently increases tyrosine hydroxylase expression and subsequently results in behavioral abnormalities in prepulse inhibition of acoustic startle, locomotor activity, and social interaction after development. The enhanced locomotor and stereotypic responses of the neonatally EGF-treated rats are considered to be an animal model for positive schizophrenia symptoms. In the present study, we investigated psychostimulant sensitivity of neonatally EGF-treated rats. At the adult stage, EGF-treated rats were challenged with cocaine (15 mg/kg) or methamphetamine (1 mg/kg), and conditioned place preference and locomotor activity were examined. The rats that received EGF during the neonatal period had significantly higher conditioned place preference for where cocaine or methamphetamine was administered than controls. The neonatal EGF treatment enhanced behavioral response to methamphetamine and behavioral sensitization to cocaine at the adult stage. Drug-naive controls gradually increased locomotor responses to cocaine during their daily injections, whereas EGF-treated rats exhibited a larger increase in cocaine responses. These results indicate that overactivation of the EGF receptors (ErbB1) during the neonatal period influences future sensitivity to psychostimulants. Our findings indicate a potential link between EGF-receptor activation and drug addiction. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 10 | Ann. N. Y. Acad. Sci. 2004 Oct 1025: 612-8 |
| PMID | 15542770 |
| Title | Conditioned place preference and locomotor sensitization after repeated administration of cocaine or methamphetamine in rats treated with epidermal growth factor during the neonatal period. |
| Abstract | Epidermal growth factor (EGF) and its structurally related proteins are involved in the developmental regulation of various brain neurons, including midbrain dopaminergic neurons. We recently reported EGF and EGF-receptor abnormalities in both the brain tissues and blood of schizophrenic patients. Administration of EGF to neonatal rats transiently increases tyrosine hydroxylase expression and subsequently results in behavioral abnormalities in prepulse inhibition of acoustic startle, locomotor activity, and social interaction after development. The enhanced locomotor and stereotypic responses of the neonatally EGF-treated rats are considered to be an animal model for positive schizophrenia symptoms. In the present study, we investigated psychostimulant sensitivity of neonatally EGF-treated rats. At the adult stage, EGF-treated rats were challenged with cocaine (15 mg/kg) or methamphetamine (1 mg/kg), and conditioned place preference and locomotor activity were examined. The rats that received EGF during the neonatal period had significantly higher conditioned place preference for where cocaine or methamphetamine was administered than controls. The neonatal EGF treatment enhanced behavioral response to methamphetamine and behavioral sensitization to cocaine at the adult stage. Drug-naive controls gradually increased locomotor responses to cocaine during their daily injections, whereas EGF-treated rats exhibited a larger increase in cocaine responses. These results indicate that overactivation of the EGF receptors (ErbB1) during the neonatal period influences future sensitivity to psychostimulants. Our findings indicate a potential link between EGF-receptor activation and drug addiction. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 11 | Behav. Genet. 2005 Sep 35: 615-29 |
| PMID | 16184489 |
| Title | Distinct influences of neonatal epidermal growth factor challenge on adult neurobehavioral traits in four mouse strains. |
| Abstract | Epidermal growth factor (EGF) receptor (ErbB1) signals regulate dopaminergic development and function and are implicated in schizophrenia. We evaluated genetic effects on neurobehavioral changes induced by neonatal EGF administration, using four mouse strains. Subcutaneous EGF administration increased phosphorylation of brain ErbB1 in all strains, although DBA/2 and C57BL/6 mice had lower basal phosphorylation. Neonatal EGF treatment differentially influenced physical and behavioral/cognitive development, depending on mouse strain. Prepulse inhibition was decreased in DBA/2 and C57BL/6 mice but not C3H/He and ddY mice. Locomotor activity was accelerated in DBA/2 mice, but reduced in ddY mice. EGF treatment enhanced fear-learning performance with a tone cue in DBA/2 mice, but decreased performance with tone and context cues in C3H/He and ddY mice, respectively. The strain-dependent behavioral sensitivity was correlated with basal ErbB1 phosphorylation. Genetic components regulating brain ErbB1 signaling strongly influence the direction and strength of behavioral responses stemming from the neonatal neurotrophic perturbation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 12 | Psychiatry Res 2005 Jun 135: 257-60 |
| PMID | 15993491 |
| Title | No changes in serum epidermal growth factor levels in patients with schizophrenia. |
| Abstract | A recent report demonstrated that serum levels of epidermal growth factor (EGF) were significantly decreased in patients with schizophrenia, suggesting that impaired EGF signaling might be associated with the pathophysiology of schizophrenia. Our goal in the present study was to determine whether serum levels of EGF are altered in patients with schizophrenia. We found that serum levels of EGF in drug-naive (n = 15) or medicated patients (n = 25) with schizophrenia did not differ from those of age- and sex-matched normal controls (n = 40). However, we found a significant correlation between serum EGF levels and BPRS scores in the combined groups of patients. Therefore, our results do not support the claim that EGF plays a role in the pathogenesis of schizophrenia, but they suggest that EGF may serve as a state marker, that is, as an index of symptom-linked deficits. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 13 | Neuroreport 2005 Mar 16: 403-5 |
| PMID | 15729146 |
| Title | No association of EGF polymorphism with schizophrenia in a Japanese population. |
| Abstract | Epidermal growth factor (EGF) signal regulates the development of dopaminergic neurons and monoamine metabolism. It is suggested that EGF protein levels are decreased in the brain and blood of patients with schizophrenia. A recent study has reported that a polymorphism in EGF gene (rs4444903) is associated with schizophrenia in Finnish men. To confirm this association for another population in larger samples, we conducted a case-control association study on a Japanese population (337 cases and 421 controls). No significant difference was observed in both the allelic and genotype distribution between cases and controls in women, men and total samples. Our results suggest that the polymorphism in EGF gene might not confer increased susceptibility for schizophrenia in a Japanese population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 14 | Eur Arch Psychiatry Clin Neurosci 2005 Aug 255: 279-83 |
| PMID | 15614591 |
| Title | Interaction of tumor necrosis alpha - G308A and epidermal growth factor gene polymorphisms in early-onset schizophrenia. |
| Abstract | The study population comprised 94 Finnish patients with DSM-IV diagnosis of schizophrenia. The patients were placed into two subgroups according to medication response to conventional neuroleptics. The aim of the study was to examine the frequency of tumor necrosis factor -308 (G > A) polymorphism in these patients and their 98 control subjects who were age- and gender-matched blood donors. Associations between TNFalpha -308 polymorphism alone and between the interaction of TNFalpha and epidermal growth factor gene polymorphisms, and medication response and age at onset of schizophrenia were also studied. The frequencies of TNFalpha A-allele were 11.7 % in patients and 12.8% in controls. The difference was not significant (p = 0.75). TNFalpha -308 polymorphism was not associated with medication response. However, patients with EGF AA and TNFalpha AG/AA genotype had a lower age at onset of schizophrenia compared with the rest of the patients not having this combination (20.0 years, 3.3 vs. 30.2 years, 10.1 mean + SD; p < 0.001). The results support earlier findings according to which TNFalpha polymorphism is not associated with the incidence of schizophrenia. On the other hand, the role of cytokines in schizophrenia may involve genetic interactions predisposing early onset of illness. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 15 | Neurosci. Lett. 2005 Feb 374: 157-60 |
| PMID | 15663953 |
| Title | Epidermal growth factor gene polymorphism is different between schizophrenia and lung cancer patients in Korean population. |
| Abstract | Low incidence of cancer in schizophrenia is one of the interesting puzzles in psychiatric field over decades. Analysis of genetic difference between schizophrenia and lung cancer might provide us with possible clues to understand molecular mechanisms of pathophysiology of schizophrenia. Epidermal growth factor (EGF), one of the potent growth promoting factors, has been studied for its roles in cancer development. EGF is also known to be involved in cognitive function. In order to analyze the genetic difference between schizophrenia and lung cancer, polymorphism of EGF gene was studied from 174 schizophrenia patients, 122 lung cancer patients and 132 controls in Korean population. Genotype frequency analysis of EGF gene (AluI restriction site, 5'-UTR, rs4444903) in the EGF gene was studied. The genotype and allele frequencies of the AluI polymorphism showed significant differences between schizophrenia and lung cancer patients [p<0.0001; p<0.0001, odds ratio (95% CI), 0.3690 (0.2600-0.5236)]. When compared with controls, schizophrenia patients showed no significant differences from controls in genotype and allele frequencies [p=0.5151; p=0.3516, odds ratio (95% CI), 0.8589 (0.6235-1.1830)]. However, lung cancer patients showed significant differences from controls in genotype and allele frequencies [p<0.0001; p<0.0001, odds ratio (95% CI), 2.3275 (1.6082-3.3687)]. These results indicate that schizophrenia is not associated with AluI polymorphism of EGF gene and EGF gene polymorphism is different between schizophrenia and lung cancer patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 16 | Neurosci. Res. 2006 Dec 56: 356-62 |
| PMID | 16979250 |
| Title | Partial evidence of an association between epidermal growth factor A61G polymorphism and age at onset in male schizophrenia. |
| Abstract | Epidermal growth factor (EGF) is a well-known neurotrophic factor regulating the development of various neuronal cells, including dopaminergic neurons, and dysfunction of EGF signals has been demonstrated as a risk factor for schizophrenia. Recently, several researchers have investigated associations including age at onset (AAO) with EGF A61G functional polymorphism, but the results of these studies have been controversial. Thus, we investigated whether A61G plays a role in predisposition to schizophrenia and its effects on AAO. Our subjects included 190 patients with schizophrenia and 347 controls. We assessed three different points of AAO: age at first occurrence of positive psychotic symptoms, medication, and hospitalization as a patient with schizophrenia. We found no differences in allele and genotype frequencies between patients and controls or associations between A61G and AAOs across stratified points in the entire sample and in each gender. However, we found significant gender differences in patients with the AA genotype in all stratified points of AAOs. Subset analyses of G allele distribution between clinical subsets with an AAO cutoff of 20 years revealed that male patients with early onset schizophrenia were more likely to exhibit the common AA homozygote than male patients with adulthood onset schizophrenia. In conclusion, although we were unable to support an association between EGF A61G and schizophrenia, the AA genotype might play a disease-modifying role differentially according to gender. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 17 | Psychopharmacology (Berl.) 2007 Apr 191: 783-92 |
| PMID | 17096084 |
| Title | Neonatal exposure to epidermal growth factor induces dopamine D2-like receptor supersensitivity in adult sensorimotor gating. |
| Abstract | Abnormality in the neurotrophic factor for dopamine neurons, epidermal growth factor (EGF), is associated with schizophrenia. Thus, rats treated with EGF as neonates are used as a putative animal model for schizophrenia showing impaired prepulse inhibition (PPI) and other cognitive deficits in the adult stage. To elucidate the abnormal behavioral traits of this animal model, the EGF effects on the dopaminergic system were analyzed pharmacologically and biochemically at the adult stage. We examined the effects of subthreshold doses of dopamine agonists on PPI in this model. A non-selective dopamine agonist, apomorphine (0.1 mg/kg), decreased PPI in EGF-treated rats, but not in controls. Further, a D(2)-like receptor agonist, quinpirole (0.01 and 0.03 mg/kg), similarly decreased PPI in EGF-treated rats but had no effect in the control animals. In contrast, a D(1)-like receptor agonist, SKF38393 (3 and 10 mg/kg), had no effect on PPI in both groups. To explore the molecular mechanism underlying the change in sensorimotor gating, we assessed D(1) and D(2) receptors expression in the prefrontal cortex, striatum and hippocampus and their downstream signaling. Although there were no significant differences in basal receptor levels, quinpirole administration significantly enhanced phosphorylation of extracellular signal-regulated kinase (ERK) and cAMP response element binding protein (CREB) in the striatum of EGF-treated rats. These results suggest that circulating EGF in the early development substantially influences D(2) receptor-dependent regulation of sensorimotor gating. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 18 | J. Neurosci. 2007 Sep 27: 10116-27 |
| PMID | 17881518 |
| Title | A cyclooxygenase-2 inhibitor ameliorates behavioral impairments induced by striatal administration of epidermal growth factor. |
| Abstract | Consistent with the hypothesis that neuroinflammatory processes contribute to the neuropathology of schizophrenia, the protein levels of epidermal growth factor (EGF) and its receptor ErbB1 are abnormal in patients with schizophrenia. To evaluate neuropathological significance of this abnormality, we established an animal model for behavioral deficits by administering EGF into the striatum and evaluated the effects of cyclooxygenase-2 (Cox-2) inhibitor celecoxib. Intracranial infusion of EGF into the striatum of adult male rats activated ErbB1 and induced neurobehavioral impairments observed in several schizophrenia models. Unilateral EGF infusion to the striatum lowered prepulse inhibition (PPI) in a dose-dependent manner and impaired latent learning of active shock avoidance without affecting basal learning ability. Bilateral EGF infusion similarly affected PPI. In contrast, EGF infusion to the nucleus accumbens did not induce a behavioral deficit. Intrastriatal EGF infusion also increased Cox-2 expression, elevated tyrosine hydroxylase activity, and upregulated the levels of dopamine and its metabolites. Subchronic administration of celecoxib (10 mg/kg, p.o.) ameliorated the abnormalities in PPI and latent learning as well as normalized dopamine metabolism. We conclude that this EGF-triggered neuroinflammatory process is mediated in part by Cox-2 activity and perturbs dopamine metabolism to generate neurobehavioral abnormalities. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 19 | J. Biol. Chem. 2007 Aug 282: 24343-51 |
| PMID | 17565985 |
| Title | Molecular cloning of a brain-specific, developmentally regulated neuregulin 1 (NRG1) isoform and identification of a functional promoter variant associated with schizophrenia. |
| Abstract | Neuregulin 1 (NRG1) is essential for the development and function of multiple organ systems, and its dysregulation has been linked to diseases such as cancer and schizophrenia. Recently, altered expression of a novel isoform (type IV) in the brain has been associated with schizophrenia-related genetic variants, especially rs6994992 (SNP8NRG243177). Here we have isolated and characterized full-length NRG1 type IV cDNAs from the adult and fetal human brain and identified novel splice variants of NRG1. Full-length type IV spans 1.8 kb and encodes a putative protein of 590 amino acids with a predicted molecular mass of approximately 66 kDa. The transcript consists of 11 exons with an Ig-like domain, an epidermal growth factor-like (EGF) domain, a beta-stalk, a transmembrane domain, and a cytoplasmic "a-tail," placing it in the beta1a NRG1 subclass. NRG1 type IV was not detected in any tissues except brain and a putative type IV NRG1 protein of 66 kDa was similarly brain-specific. Type IV transcripts are more abundantly expressed in the fetal brain, where, in addition to the full-length structure, two novel type IV variants were identified. In vitro luciferase-reporter assays demonstrate that the 5' promoter region upstream of type IV is functional, with differential activity associated with genetic variation at rs6994992, and that promoter competition may impact on type IV expression. Our data suggest that type IV is a unique brain-specific NRG1 that is differentially expressed and processed during early development, is translated, and its expression regulated by a schizophrenia risk-associated functional promoter or single nucleotide polymorphism (SNP). |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 20 | Adv Anat Embryol Cell Biol 2007 -1 190: 1-65 |
| PMID | 17432114 |
| Title | The neuregulin-I/ErbB signaling system in development and disease. |
| Abstract | Neuregulins (NRGs) comprise a large family of EGF-like signaling molecules involved in cell-cell communication during development and disease. The neuregulin family of ligands has four members: NRG1, NRG2, NRG3, and NRG4. Relatively little is known about the biological functions of the NRG2, 3, and 4 proteins. In contrast, the NRG1 proteins have been demonstrated to play important roles during the development of the nervous system, heart, and mammary glands. For example, NRG1 has essential functions in the development of neural crest cells and some of their major derivatives, like Schwann cells and sympathetic neurons. NRG1 controls the trabeculation of the myocardial musculature and the ductal differentiation of the mammary epithelium. Moreover, there is emerging evidence for the involvement of NRG signals in the development and function of several other organ systems, and in human disease, including breast cancer and schizophrenia. Many different isoforms of the Neuregulin-1 gene are synthesized. Such isoforms differ in their tissue-specific expression patterns and their biological activities, thereby contributing to the great diversity of the in vivo functions of NRG1. Neuregulins transmit their signals to target cells by interacting with transmembrane tyrosine kinase receptors of the ErbB family. This family includes four members, the epidermal growth factor receptor (EGF-R, ErbB1, ErbB2, ErbB3, and ErbB4). Receptor-ligand interaction induces the heterodimerization of receptor monomers, which in turn results in the activation of intracellular signaling cascades and the induction of cellular responses including proliferation, migration, differentiation, and survival or apoptosis. In vivo, functional NRG1 receptors are heterodimers composed of ErbB2 with either an ErbB3, or ErbB4 molecule. The tissue-specific distribution of the different receptor types further contributes to the diversity and specificity of the biological functions of this signaling pathway. It is a typical feature of the Neuregulin-1/ErbB signaling pathway to control sequential steps during the development of a particular organ system. For example, this pathway functions in early precursor proliferation, maturation, as well as in the myelination of Schwann cells. The systematic analysis of genetic models that have been established by the help of conventional as well as conditional gene targeting strategies in mice was instrumental for the uncovering of the multitude of biological functions of this signaling system. In this review the basic biology of the Neuregulin-1/ErbB system and how it relates to the in vivo functions were discussed with special emphasis to transgenic techniques in mice. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 21 | Ann. N. Y. Acad. Sci. 2007 Jan 1096: 147-56 |
| PMID | 17405926 |
| Title | Immunohistochemical evidence for impaired neuregulin-1 signaling in the prefrontal cortex in schizophrenia and in unipolar depression. |
| Abstract | In the central nervous system (CNS), neuregulin-1 (NRG-1) proteins function in neuronal migration, differentiation, and survival of oligodendrocytes. The NRG-1 gene codes for at least 15 different isoforms, which may be classified on the basis of their molecular structure. At least two different haplotypes of the NRG-1 gene may be associated with schizophrenia. An abnormal expression pattern of NRG-1 mRNA was found in the prefrontal cortex of schizophrenic patients in comparison to controls. We here show that the NRG-1alpha isoform is significantly reduced in white matter of the prefrontal cortex in schizophrenia but not in affective disorder. In the prefrontal gray matter, the density of NRG-1alpha expressing neurons was reduced in individuals with schizophrenia and in unipolar patients. We studied brains of 22 schizophrenics, 12 patients with affective disorders (7 unipolar and 5 bipolar), and 22 matched controls. NRG-1alpha immunoreactive material was detected with a polyclonal antiserum against the synthetic peptide from alpha-type EGF-like domain of human NRG. The demonstrated decreased number of NRG-1 immunoreactive neurons in the brains of schizophrenics and patients with unipolar depression points to an important role of this NRG-1alpha splice variant in neuropsychiatric disorders. Reduced NRG-1alpha protein concentrations were found in brains of schizophrenics after Western blot analysis. The diminished expression of NRG-1alpha strongly supports an early neurodevelopmental component to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 22 | Ann. N. Y. Acad. Sci. 2007 Jan 1096: 147-56 |
| PMID | 17405926 |
| Title | Immunohistochemical evidence for impaired neuregulin-1 signaling in the prefrontal cortex in schizophrenia and in unipolar depression. |
| Abstract | In the central nervous system (CNS), neuregulin-1 (NRG-1) proteins function in neuronal migration, differentiation, and survival of oligodendrocytes. The NRG-1 gene codes for at least 15 different isoforms, which may be classified on the basis of their molecular structure. At least two different haplotypes of the NRG-1 gene may be associated with schizophrenia. An abnormal expression pattern of NRG-1 mRNA was found in the prefrontal cortex of schizophrenic patients in comparison to controls. We here show that the NRG-1alpha isoform is significantly reduced in white matter of the prefrontal cortex in schizophrenia but not in affective disorder. In the prefrontal gray matter, the density of NRG-1alpha expressing neurons was reduced in individuals with schizophrenia and in unipolar patients. We studied brains of 22 schizophrenics, 12 patients with affective disorders (7 unipolar and 5 bipolar), and 22 matched controls. NRG-1alpha immunoreactive material was detected with a polyclonal antiserum against the synthetic peptide from alpha-type EGF-like domain of human NRG. The demonstrated decreased number of NRG-1 immunoreactive neurons in the brains of schizophrenics and patients with unipolar depression points to an important role of this NRG-1alpha splice variant in neuropsychiatric disorders. Reduced NRG-1alpha protein concentrations were found in brains of schizophrenics after Western blot analysis. The diminished expression of NRG-1alpha strongly supports an early neurodevelopmental component to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 23 | Ann. N. Y. Acad. Sci. 2007 Jan 1096: 147-56 |
| PMID | 17405926 |
| Title | Immunohistochemical evidence for impaired neuregulin-1 signaling in the prefrontal cortex in schizophrenia and in unipolar depression. |
| Abstract | In the central nervous system (CNS), neuregulin-1 (NRG-1) proteins function in neuronal migration, differentiation, and survival of oligodendrocytes. The NRG-1 gene codes for at least 15 different isoforms, which may be classified on the basis of their molecular structure. At least two different haplotypes of the NRG-1 gene may be associated with schizophrenia. An abnormal expression pattern of NRG-1 mRNA was found in the prefrontal cortex of schizophrenic patients in comparison to controls. We here show that the NRG-1alpha isoform is significantly reduced in white matter of the prefrontal cortex in schizophrenia but not in affective disorder. In the prefrontal gray matter, the density of NRG-1alpha expressing neurons was reduced in individuals with schizophrenia and in unipolar patients. We studied brains of 22 schizophrenics, 12 patients with affective disorders (7 unipolar and 5 bipolar), and 22 matched controls. NRG-1alpha immunoreactive material was detected with a polyclonal antiserum against the synthetic peptide from alpha-type EGF-like domain of human NRG. The demonstrated decreased number of NRG-1 immunoreactive neurons in the brains of schizophrenics and patients with unipolar depression points to an important role of this NRG-1alpha splice variant in neuropsychiatric disorders. Reduced NRG-1alpha protein concentrations were found in brains of schizophrenics after Western blot analysis. The diminished expression of NRG-1alpha strongly supports an early neurodevelopmental component to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 24 | Schizophr. Res. 2008 Apr 101: 58-66 |
| PMID | 18289832 |
| Title | Low serum levels of brain-derived neurotrophic factor and epidermal growth factor in patients with chronic schizophrenia. |
| Abstract | Neurotrophic factors (NFs) play a pivotal role in the development of the central nervous system. They are thus also suspected of being involved in the etiology of schizophrenia. Previous studies reported a decreased level of serum brain-derived neurotrophic factor (BDNF) in schizophrenia, whereas the association of epidermal growth factor (EGF) with this illness remains controversial. Using a two-site enzyme immunoassay, we conducted the simultaneous measurement of serum BDNF and EGF levels in a group of patients with chronic schizophrenia (N=74) and a group of normal controls matched in age, body mass index, smoking habit and sex (N=87). We found that, compared to normal controls, patients with chronic schizophrenia exhibited lower serum levels of both BDNF and EGF across all ages examined (21-59 years). The serum levels of BDNF and EGF were negatively correlated in the controls (r=-0.387, P=0.0002) but not in the patients. Clinical parameters such as duration of illness and psychiatric rating scale also showed no robust correlations with the NF levels. Collectively, these results suggest that pervasive, abnormal signaling of NFs underlies the pathophysiology of chronic schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 25 | Behav. Neurosci. 2008 Aug 122: 748-59 |
| PMID | 18729627 |
| Title | Behavioral profile of a heterozygous mutant mouse model for EGF-like domain neuregulin 1. |
| Abstract | Human genetic studies have demonstrated that the neuregulin 1 gene (NRG1) is involved in the development of schizophrenia. Alternative splicing of NRG1 results in at least 15 distinct isoforms and all contain an extracellular epidermal growth factor (EGF)-like domain, which is sufficient for Nrg1's biological activity. Here, we characterize a heterozygous mutant model for mouse EGF-like domain neuregulin 1 (Nrg1) regarding schizophrenia-related behavioral domains. A comprehensive, multitiered phenotyping strategy was used to investigate locomotion, exploration, anxiety-related behaviors, and sensorimotor gating. Nrg1 mutant mice exhibited a hyper-locomotive phenotype and an improved ability to habituate to a new environment. Extensive analysis of anxiety-related behaviors revealed a wild type-like phenotype in this domain. However, a moderate impairment in sensorimotor gating was found after pharmacological challenge using psychoactive substances. Our study adds to the increasing behavioral data available from a variety of animal models for Nrg1 isoforms. We suggest a standardized and comprehensive behavioral phenotyping approach to distinguish between the different models and to clarify their relevance for schizophrenia research. Future behavioral investigations will focus on the negative and cognitive symptoms of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 26 | J Neural Transm (Vienna) 2008 -1 115: 521-30 |
| PMID | 18301953 |
| Title | The anthraquinone derivative Emodin ameliorates neurobehavioral deficits of a rodent model for schizophrenia. |
| Abstract | Abnormality in cytokine signaling is implicated in the neuropathology of schizophrenia. Previously, we established an animal model for schizophrenia by administering epidermal growth factor (EGF) to neonatal rats. Here we investigated effects of the anthraquinone derivatives emodin (3-methyl-1,6,8-trihydroxyanthraquinone) and sennoside (bis-[D: -glucopyranosyl-oxy]-tetrahydro-4,4'-dihydroxy-dioxo[bianthracene]-2,2'-dicarboxylic acid) on behaviors of this model and EGF signaling. Subchronic oral administration of emodin (50 mg/kg) suppressed acoustic startle responses and abolished prepulse inhibition (PPI) deficits in this rodent model. ANCOVA revealed that emodin had distinct effects on PPI and startle responses. In contrast, sennoside (50 mg/kg) had no effects. Emodin attenuated weight gain initially during treatment but had no apparent effect on weight gain and locomotor activity thereafter. Application of emodin to neocortical cultures attenuated the phosphorylation of ErbB1 and ErbB2. We conclude that emodin can both attenuate EGF receptor signaling and ameliorate behavioral deficits. Therefore, emodin might be a novel class of a pro-drug for anti-psychotic medication. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 27 | Brain Dev. 2008 Sep 30: 533-43 |
| PMID | 18313247 |
| Title | Common behavioral influences of the ErbB1 ligands transforming growth factor alpha and epiregulin administered to mouse neonates. |
| Abstract | Ligands for epidermal growth factor (EGF) receptor (ErbB1), such as EGF, transforming growth factor alpha (TGFalpha), and epiregulin, are enriched in body fluids and blood and regulate development of various peripheral organs. It remains however how such circulating polypeptide growth factors influence brain development and function. Here, we performed peripheral injections of TGFalpha and epiregulin to mouse neonates and evaluated immediate physical and neurochemical development and later behavioral consequences. Subcutaneous administration of TGFalpha and epiregulin increased phosphorylation of brain ErbB1, suggesting their effects on brain development. Repeated their injections similarly enhanced physical development of eyelid opening and tooth eruption during early postnatal stage and resulted in abnormal behavioral traits in the adult stage. Acoustic startle responses of mice treated with these growth factors as neonates were enhanced and prepulse inhibition was decreased without an apparent correlation between prepulse inhibition level and startle intensity. Locomotor activity and fear-learning performance with tone and context cues were not altered, however. These results suggest that circulating ErbB1 ligands in the periphery of neonates have some common influences on later behavioral traits. Abnormal ErbB1 ligand production at neonatal and potentially prenatal stages might therefore associate with neurodevelopmental disorders such as schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 28 | PLoS ONE 2009 -1 4: e7461 |
| PMID | 19829704 |
| Title | Generation and characterization of conditional heparin-binding EGF-like growth factor knockout mice. |
| Abstract | Recently, neurotrophic factors and cytokines have been shown to be associated in psychiatric disorders, such as schizophrenia, bipolar disorder, and depression. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a member of the EGF family, serves as a neurotrophic molecular and plays a significant role in the brain. We generated mice in which HB-EGF activity is disrupted specifically in the ventral forebrain. These knockout mice showed (a) behavioral abnormalities similar to those described in psychiatric disorders, which were ameliorated by typical or atypical antipsychotics, (b) altered dopamine and serotonin levels in the brain, (c) decreases in spine density in neurons of the prefrontal cortex, (d) reductions in the protein levels of the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor and post-synaptic protein-95 (PSD-95), (e) decreases in the EGF receptor, and in the calcium/calmodulin-dependent protein kinase II (CaMK II) signal cascade. These results suggest the alterations affecting HB-EGF signaling could comprise a contributing factor in psychiatric disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 29 | Exp. Cell Res. 2009 Feb 315: 611-8 |
| PMID | 19046966 |
| Title | ErbB receptors and the development of the nervous system. |
| Abstract | Tyrosine kinase receptors and their ligands allow communication between cells in the developing and adult organism. An extensive line of research has revealed that 'neuregulins', a family of EGF-like factors that signal via ErbB receptors, are used frequently for cell communication during nervous system development, and control a spectacular spectrum of developmental processes. For instance, during development of the peripheral nervous system, Schwann cells require neuronally-produced neuregulin (Nrg1) for growth, migration and myelination, neural crest cells rely on mesenchymally-generated Nrg1 signals for migration, while muscle requires neuronally-produced Nrg1 for the differentiation of a muscle spindle. In the central nervous system, neuregulin signals allow cells to act as guideposts or as barriers for axons during pathfinding. Neuregulin signals are also important in other organs, but the nervous system functions have received recently considerable attention due to the finding that particular haplotypes of Nrg1 and ErbB4 predispose to schizophrenia. Understanding the neuregulin signaling system can thus contribute to define causes of this devastating mental disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 30 | Encephale 2009 Sep 35: 347-52 |
| PMID | 19748371 |
| Title | [Schizophrenia and violence, incidence and risk factors: a Tunisian sample]. |
| Abstract | schizophrenia appears to be the mental pathology the most associated with violence. The aim of this study is to show the incidence and the different risk factors of violence among schizophrenics. We have compared a group of 30 violent schizophrenic inpatients with another group of 30 nonviolent schizophrenic inpatients hospitalised during the same period. These two groups have been matched according to age and gender. The comparison concerned: sociodemographic parameters, family and personal psychiatric history, legal antecedents, social insertion, clinic, Clinical Global Impressions (CGI), Global Impairment Scale (GIS) and Positive And Negative Syndrome Scale (PANSS) scores for admissions, familial support and insight, compliance to treatment, administered treatments, and awareness degree. Violent schizophrenics represent 18.07% of all hospitalisations and 26.08% of schizophrenic patients. When compared to violent schizophrenic patients, nonviolent schizophrenic patients have a better socioeconomic level (77% versus 43%), better professional adaptation (67% versus 10%) and familial support (60% versus 10%), better insight (87% versus 23%) and therapeutic control (70% versus 17%). Differences are significant. We found significantly more personal antecedents of inflicted violence within violent schizophrenics (50% versus 13%), more addictive behavior (53% versus 13%), and more paranoid and indifferentiated forms (87% versus 47%) than in nonviolent schizophrenics. The average of CGI scores was significantly higher within violent schizophrenics (5.27+/-0.8 versus 3.77+/-0.5). Conversely, the average of EGF scores was lowest (37.6+/-6.5 versus 47.8+/-5.6). The comparison of PANSS scores revealed that violent schizophrenic subjects are characterised by the existence of more positive signs and more general symptoms (34.4+/-4.7 versus 20.2+/-4.5; 55.1+/-11.4 versus 46.1+/-6.9). Violent schizophrenics are characterised by higher neuroleptic doses (2375+/-738 mg/d versus 1610+/-434 mg/d). Differences here are also significant. Addictive behaviour seems to considerably increase the risk of turning to violence. Thus in our study, 53% of violent patients showed an addictive behaviour. These results have also been reported by other authors. It is obvious that alcohol and drug abuse double the risk of violence among schizophrenic subjects. Psychotic decompensation and rich symptomatology increase the violent potential among the schizophrenics. In our study, the PANSS scores were higher among violent subjects. Nonviolent schizophrenic subjects have a lesser symptomatology of psychiatric disorders and a better outcome as shown by the CGI and EGF scores. In our study, the group of violent subjects needed higher neuroleptic doses and were noncompliant. Compliance permits the acquisition, and then maintains, the stability of the mental status and plays an essential role in decreasing dangerousness. In fact, violent schizophrenics exhibit low insight, implying diminished awareness of the legal implications of their acts, and are little aware of their illness and its dangerousness. In our study, we noted better familial support among nonviolent subjects. According to the literature, violent schizophrenics are characterised by a particularly hostile and rejecting familial environment. Awareness of these factors will allow us to provide improved prevention of violence within schizophrenic subjects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 31 | Encephale 2009 Sep 35: 347-52 |
| PMID | 19748371 |
| Title | [Schizophrenia and violence, incidence and risk factors: a Tunisian sample]. |
| Abstract | schizophrenia appears to be the mental pathology the most associated with violence. The aim of this study is to show the incidence and the different risk factors of violence among schizophrenics. We have compared a group of 30 violent schizophrenic inpatients with another group of 30 nonviolent schizophrenic inpatients hospitalised during the same period. These two groups have been matched according to age and gender. The comparison concerned: sociodemographic parameters, family and personal psychiatric history, legal antecedents, social insertion, clinic, Clinical Global Impressions (CGI), Global Impairment Scale (GIS) and Positive And Negative Syndrome Scale (PANSS) scores for admissions, familial support and insight, compliance to treatment, administered treatments, and awareness degree. Violent schizophrenics represent 18.07% of all hospitalisations and 26.08% of schizophrenic patients. When compared to violent schizophrenic patients, nonviolent schizophrenic patients have a better socioeconomic level (77% versus 43%), better professional adaptation (67% versus 10%) and familial support (60% versus 10%), better insight (87% versus 23%) and therapeutic control (70% versus 17%). Differences are significant. We found significantly more personal antecedents of inflicted violence within violent schizophrenics (50% versus 13%), more addictive behavior (53% versus 13%), and more paranoid and indifferentiated forms (87% versus 47%) than in nonviolent schizophrenics. The average of CGI scores was significantly higher within violent schizophrenics (5.27+/-0.8 versus 3.77+/-0.5). Conversely, the average of EGF scores was lowest (37.6+/-6.5 versus 47.8+/-5.6). The comparison of PANSS scores revealed that violent schizophrenic subjects are characterised by the existence of more positive signs and more general symptoms (34.4+/-4.7 versus 20.2+/-4.5; 55.1+/-11.4 versus 46.1+/-6.9). Violent schizophrenics are characterised by higher neuroleptic doses (2375+/-738 mg/d versus 1610+/-434 mg/d). Differences here are also significant. Addictive behaviour seems to considerably increase the risk of turning to violence. Thus in our study, 53% of violent patients showed an addictive behaviour. These results have also been reported by other authors. It is obvious that alcohol and drug abuse double the risk of violence among schizophrenic subjects. Psychotic decompensation and rich symptomatology increase the violent potential among the schizophrenics. In our study, the PANSS scores were higher among violent subjects. Nonviolent schizophrenic subjects have a lesser symptomatology of psychiatric disorders and a better outcome as shown by the CGI and EGF scores. In our study, the group of violent subjects needed higher neuroleptic doses and were noncompliant. Compliance permits the acquisition, and then maintains, the stability of the mental status and plays an essential role in decreasing dangerousness. In fact, violent schizophrenics exhibit low insight, implying diminished awareness of the legal implications of their acts, and are little aware of their illness and its dangerousness. In our study, we noted better familial support among nonviolent subjects. According to the literature, violent schizophrenics are characterised by a particularly hostile and rejecting familial environment. Awareness of these factors will allow us to provide improved prevention of violence within schizophrenic subjects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 32 | Neurochem. Int. 2009 Dec 55: 606-9 |
| PMID | 19524002 |
| Title | Neuregulin 1-stimulated phosphorylation of AKT in psychotic disorders and its relationship with neurocognitive functions. |
| Abstract | Neuregulin 1 (NRG1) has been implicated in the pathophysiology of psychotic disorders. NRG1 exerts its effects via the Ras-MAPK and phosphatidylinositol-3 kinase-protein kinase B (PI3K-PKB/AKT) intracellular signaling pathways through ErbB receptors. The aim of this study was to investigate the relationship between NRG1-stimulated AKT phosphorylation and neurocognitive functions in patients with schizophrenia and in patients with other psychotic disorders. B lymphoblasts of patients (n=40) and controls (n=20) were stimulated with NRG1a (65 amino-acid residue recombinant protein from the epidermal growth factor [EGF] domain) for 30-min. The protein isolated from the cells was analyzed by Western blotting. The dependent measure was the ratio of phosphorylated AKT (pAKT) and total AKT at baseline (without NRG1 stimulation) and after NRG1 stimulation (pAKT/AKT). The neurocognitive functions (attention, immediate and long-term memory, language, visual-spatial skills) were evaluated by the repeatable brief assessment of neuropsychological status (RBANS) battery. The results revealed a significantly reduced pAKT/AKT ratio in patients with schizophrenia as compared with healthy controls and with patients with other psychotic disorders. The patients with other psychotic disorders did not differ from the healthy controls. Despite the fact that neurocognitive functions were significantly impaired in the patients, these functions did not reveal significant correlations with the pAKT/AKT ratio. In conclusion, NRG1-induced AKT phosphorylation is decreased in schizophrenia but not in other psychotic disorders. This peripheral marker is not related to neurocognitive functions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 33 | Neuroscience 2009 Jun 161: 95-110 |
| PMID | 19298847 |
| Title | In situ hybridization reveals developmental regulation of ErbB1-4 mRNA expression in mouse midbrain: implication of ErbB receptors for dopaminergic neurons. |
| Abstract | Although epidermal growth factor (EGF) and neuregulin-1 are neurotrophic factors for mesencephalic dopaminergic neurons and implicated in schizophrenia, the cellular localization and developmental regulation of their receptors (ErbB1-4) remain to be characterized. Here we investigated the distributions of mRNA for ErbB1-4 in the midbrain of the developing mouse with in situ hybridization and immunohistochemistry. The expression of ErbB1 and ErbB2 mRNAs was relatively high at the perinatal stage and frequently colocalized with mRNA for S100beta and Olig2, markers for immature astrocytes or oligodendrocyte precursors. Modest signal for ErbB1 mRNA was also detected in a subset of dopaminergic neurons. ErbB3 mRNA was detectable at postnatal day 10, peaked at postnatal day 18, and colocalized with 2',3'-cyclic nucleotide 3'-phosphodiesterase, a marker for oligodendrocytes. In contrast, ErbB4 mRNA was exclusively localized in neurons throughout development. Almost all of ErbB4 mRNA-expressing cells (94%-96%) were positive for tyrosine hydroxylase in the substantia nigra pars compacta but 66%-78% in the ventral tegmental area and substantia nigra pars lateralis. Conversely, 92%-99% of tyrosine hydroxylase-positive cells expressed ErbB4 mRNA. The robust and restricted expression of ErbB4 mRNA in the midbrain dopaminergic neurons suggests that ErbB4 ligands, neuregulin-1 and other EGF-related molecules, contribute to development or maintenance of this neuronal population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 34 | J. Mol. Neurosci. 2009 Sep 39: 185-98 |
| PMID | 19277491 |
| Title | Clozapine-induced ERK1 and ERK2 signaling in prefrontal cortex is mediated by the EGF receptor. |
| Abstract | The atypical antipsychotic drug clozapine is effective in treatment-refractory schizophrenia. The intracellular signaling pathways that mediate clozapine action remain unknown. A potential candidate is the mitogen-activated protein kinase extracellular signal-regulated kinase (MAPK-ERK) cascade that links G-protein-coupled receptor and ErbB growth factor signaling systems, thereby regulating synaptic plasticity and connectivity, processes impaired in schizophrenia. Here, we examined how clozapine differentially modulated phosphorylation of the MAPK isoforms, ERK1/ERK2 in primary murine prefrontal cortical neurons compared to the typical antipsychotic drug haloperidol. While clozapine and haloperidol acutely decreased cortical pERK1 activation, only clozapine but not haloperidol stimulated pERK1 and pERK2 with continued drug exposure. This delayed ERK increase however, did not occur via the canonical dopamine D(2)-Gi/o-PKA or serotonin 5HT(2A)-Gq-phospholipase-C-linked signaling pathways. Rather, epidermal growth factor (EGF) receptor signaling mediated clozapine-induced ERK activation, given dose-dependent reduction of pERK1 and pERK2 stimulation with the EGF receptor inhibitor, AG1478. Immunocytochemical studies indicated that clozapine treatment increased EGF receptor (Tyr1068) phosphorylation. In vivo mouse treatment studies supported the in vitro findings with initial blockade, subsequent activation, and normalization of the cortical ERK response over 24 h. Furthermore, in vivo clozapine-induced ERK activation was significantly reduced by AG1478. This is the first report that clozapine action on prefrontal cortical neurons involves the EGF signaling system. Since EGF receptor signaling has not been previously linked to antipsychotic drug action, our findings may implicate the EGF system as a molecular substrate in treatment-resistant schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 35 | Encephale 2009 Sep 35: 347-52 |
| PMID | 19748371 |
| Title | [Schizophrenia and violence, incidence and risk factors: a Tunisian sample]. |
| Abstract | schizophrenia appears to be the mental pathology the most associated with violence. The aim of this study is to show the incidence and the different risk factors of violence among schizophrenics. We have compared a group of 30 violent schizophrenic inpatients with another group of 30 nonviolent schizophrenic inpatients hospitalised during the same period. These two groups have been matched according to age and gender. The comparison concerned: sociodemographic parameters, family and personal psychiatric history, legal antecedents, social insertion, clinic, Clinical Global Impressions (CGI), Global Impairment Scale (GIS) and Positive And Negative Syndrome Scale (PANSS) scores for admissions, familial support and insight, compliance to treatment, administered treatments, and awareness degree. Violent schizophrenics represent 18.07% of all hospitalisations and 26.08% of schizophrenic patients. When compared to violent schizophrenic patients, nonviolent schizophrenic patients have a better socioeconomic level (77% versus 43%), better professional adaptation (67% versus 10%) and familial support (60% versus 10%), better insight (87% versus 23%) and therapeutic control (70% versus 17%). Differences are significant. We found significantly more personal antecedents of inflicted violence within violent schizophrenics (50% versus 13%), more addictive behavior (53% versus 13%), and more paranoid and indifferentiated forms (87% versus 47%) than in nonviolent schizophrenics. The average of CGI scores was significantly higher within violent schizophrenics (5.27+/-0.8 versus 3.77+/-0.5). Conversely, the average of EGF scores was lowest (37.6+/-6.5 versus 47.8+/-5.6). The comparison of PANSS scores revealed that violent schizophrenic subjects are characterised by the existence of more positive signs and more general symptoms (34.4+/-4.7 versus 20.2+/-4.5; 55.1+/-11.4 versus 46.1+/-6.9). Violent schizophrenics are characterised by higher neuroleptic doses (2375+/-738 mg/d versus 1610+/-434 mg/d). Differences here are also significant. Addictive behaviour seems to considerably increase the risk of turning to violence. Thus in our study, 53% of violent patients showed an addictive behaviour. These results have also been reported by other authors. It is obvious that alcohol and drug abuse double the risk of violence among schizophrenic subjects. Psychotic decompensation and rich symptomatology increase the violent potential among the schizophrenics. In our study, the PANSS scores were higher among violent subjects. Nonviolent schizophrenic subjects have a lesser symptomatology of psychiatric disorders and a better outcome as shown by the CGI and EGF scores. In our study, the group of violent subjects needed higher neuroleptic doses and were noncompliant. Compliance permits the acquisition, and then maintains, the stability of the mental status and plays an essential role in decreasing dangerousness. In fact, violent schizophrenics exhibit low insight, implying diminished awareness of the legal implications of their acts, and are little aware of their illness and its dangerousness. In our study, we noted better familial support among nonviolent subjects. According to the literature, violent schizophrenics are characterised by a particularly hostile and rejecting familial environment. Awareness of these factors will allow us to provide improved prevention of violence within schizophrenic subjects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 36 | PLoS ONE 2010 -1 5: e9166 |
| PMID | 20161799 |
| Title | Plasma protein biomarkers for depression and schizophrenia by multi analyte profiling of case-control collections. |
| Abstract | Despite significant research efforts aimed at understanding the neurobiological underpinnings of psychiatric disorders, the diagnosis and the evaluation of treatment of these disorders are still based solely on relatively subjective assessment of symptoms. Therefore, biological markers which could improve the current classification of psychiatry disorders, and in perspective stratify patients on a biological basis into more homogeneous clinically distinct subgroups, are highly needed. In order to identify novel candidate biological markers for major depression and schizophrenia, we have applied a focused proteomic approach using plasma samples from a large case-control collection. Patients were diagnosed according to DSM criteria using structured interviews and a number of additional clinical variables and demographic information were assessed. Plasma samples from 245 depressed patients, 229 schizophrenic patients and 254 controls were submitted to multi analyte profiling allowing the evaluation of up to 79 proteins, including a series of cytokines, chemokines and neurotrophins previously suggested to be involved in the pathophysiology of depression and schizophrenia. Univariate data analysis showed more significant p-values than would be expected by chance and highlighted several proteins belonging to pathways or mechanisms previously suspected to be involved in the pathophysiology of major depression or schizophrenia, such as insulin and MMP-9 for depression, and BDNF, EGF and a number of chemokines for schizophrenia. Multivariate analysis was carried out to improve the differentiation of cases from controls and identify the most informative panel of markers. The results illustrate the potential of plasma biomarker profiling for psychiatric disorders, when conducted in large collections. The study highlighted a set of analytes as candidate biomarker signatures for depression and schizophrenia, warranting further investigation in independent collections. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 37 | PLoS ONE 2010 -1 5: e9166 |
| PMID | 20161799 |
| Title | Plasma protein biomarkers for depression and schizophrenia by multi analyte profiling of case-control collections. |
| Abstract | Despite significant research efforts aimed at understanding the neurobiological underpinnings of psychiatric disorders, the diagnosis and the evaluation of treatment of these disorders are still based solely on relatively subjective assessment of symptoms. Therefore, biological markers which could improve the current classification of psychiatry disorders, and in perspective stratify patients on a biological basis into more homogeneous clinically distinct subgroups, are highly needed. In order to identify novel candidate biological markers for major depression and schizophrenia, we have applied a focused proteomic approach using plasma samples from a large case-control collection. Patients were diagnosed according to DSM criteria using structured interviews and a number of additional clinical variables and demographic information were assessed. Plasma samples from 245 depressed patients, 229 schizophrenic patients and 254 controls were submitted to multi analyte profiling allowing the evaluation of up to 79 proteins, including a series of cytokines, chemokines and neurotrophins previously suggested to be involved in the pathophysiology of depression and schizophrenia. Univariate data analysis showed more significant p-values than would be expected by chance and highlighted several proteins belonging to pathways or mechanisms previously suspected to be involved in the pathophysiology of major depression or schizophrenia, such as insulin and MMP-9 for depression, and BDNF, EGF and a number of chemokines for schizophrenia. Multivariate analysis was carried out to improve the differentiation of cases from controls and identify the most informative panel of markers. The results illustrate the potential of plasma biomarker profiling for psychiatric disorders, when conducted in large collections. The study highlighted a set of analytes as candidate biomarker signatures for depression and schizophrenia, warranting further investigation in independent collections. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 38 | World J. Biol. Psychiatry 2010 Apr 11: 556-66 |
| PMID | 20218926 |
| Title | Reduced density of ADAM 12-immunoreactive oligodendrocytes in the anterior cingulate white matter of patients with schizophrenia. |
| Abstract | Abnormalities of brain white matter and oligodendroglia are replicated findings in schizophrenia research. The largely oligodendroglia-associated enzyme ADAM (A disintegrin and metalloprotease) 12 might be involved in the patho-physiology of schizophrenia, because the gene coding for human ADAM12 is located on chromosome 10q26.3, a gene locus which has been linked to schizophrenia, and some of its putative substrates are altered in schizophrenia. We studied the numerical density of ADAM12 expressing oligodendrocytes in post-mortem prefrontal brains of patients with haloperidol treated, chronic schizophrenia and matched controls. A significantly reduced numerical density of ADAM12 immunoreactive oligodendrocytes was found in the white matter of the anterior cingulate cortex of schizophrenic patients. Although the pathophysiological implications of this finding are currently unknown, it is well conveyable that reduced ADAM12 protein contributes to a deviant metabolism of some of its substrates. These substrates are either parts of important signalling cascades (EGF, betacellulin, TGF-beta) or chemical components of myelin (neurofascin-ankyrin) known to be compromised in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 39 | World J. Biol. Psychiatry 2010 Apr 11: 556-66 |
| PMID | 20218926 |
| Title | Reduced density of ADAM 12-immunoreactive oligodendrocytes in the anterior cingulate white matter of patients with schizophrenia. |
| Abstract | Abnormalities of brain white matter and oligodendroglia are replicated findings in schizophrenia research. The largely oligodendroglia-associated enzyme ADAM (A disintegrin and metalloprotease) 12 might be involved in the patho-physiology of schizophrenia, because the gene coding for human ADAM12 is located on chromosome 10q26.3, a gene locus which has been linked to schizophrenia, and some of its putative substrates are altered in schizophrenia. We studied the numerical density of ADAM12 expressing oligodendrocytes in post-mortem prefrontal brains of patients with haloperidol treated, chronic schizophrenia and matched controls. A significantly reduced numerical density of ADAM12 immunoreactive oligodendrocytes was found in the white matter of the anterior cingulate cortex of schizophrenic patients. Although the pathophysiological implications of this finding are currently unknown, it is well conveyable that reduced ADAM12 protein contributes to a deviant metabolism of some of its substrates. These substrates are either parts of important signalling cascades (EGF, betacellulin, TGF-beta) or chemical components of myelin (neurofascin-ankyrin) known to be compromised in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 40 | Pharmacol. Biochem. Behav. 2010 Dec 97: 392-8 |
| PMID | 20863847 |
| Title | The anthraquinone derivative emodin attenuates methamphetamine-induced hyperlocomotion and startle response in rats. |
| Abstract | Abnormal signaling mediated by epidermal growth factor (EGF) or its receptor (ErbB) is implicated in the neuropathology of schizophrenia. Previously, we found that the anthraquinone derivative emodin (3-methyl-1,6,8-trihydroxyanthraquinone) inhibits ErbB1 signaling and ameliorates behavioral deficits of the schizophrenia animal model established by EGF challenge. In the present study, we assessed acute and subchronic effects of its administration on methamphetamine-triggered behavioral hyperactivation in rats. Prior subchronic administration of emodin (50mg/kg/day, 5days, p.o.) suppressed both higher acoustic startle responses and hyperlocomotion induced by acute methamphetamine challenge. In parallel, emodin also attenuated methamphetamine-induced increases in dopamine and its metabolites and decreases in serotonin and its metabolites. Emodin administered alone also had an effect on stereotypic movement but no influence on horizontal or vertical locomotor activity. In contrast to pre-treatment, post-treatment with emodin had no effect on behavioral sensitization to methamphetamine. Administration of emodin in parallel to or following repeated methamphetamine challenge failed to affect hyperlocomotion induced by methamphetamine re-challenges. These findings suggest that emodin has unique pharmacological activity, which interferes with acute methamphetamine signaling and behavior. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 41 | Proc. Natl. Acad. Sci. U.S.A. 2010 Aug 107: 15619-24 |
| PMID | 20713722 |
| Title | Common genetic variation in Neuregulin 3 (NRG3) influences risk for schizophrenia and impacts NRG3 expression in human brain. |
| Abstract | Structural and polymorphic variations in Neuregulin 3 (NRG3), 10q22-23 are associated with a broad spectrum of neurodevelopmental disorders including developmental delay, cognitive impairment, autism, and schizophrenia. NRG3 is a member of the neuregulin family of EGF proteins and a ligand for the ErbB4 receptor tyrosine kinase that plays pleotropic roles in neurodevelopment. Several genes in the NRG-ErbB signaling pathway including NRG1 and ErbB4 have been implicated in genetic predisposition to schizophrenia. Previous fine mapping of the 10q22-23 locus in schizophrenia identified genome-wide significant association between delusion severity and polymorphisms in intron 1 of NRG3 (rs10883866, rs10748842, and rs6584400). The biological mechanisms remain unknown. We identified significant association of these SNPs with increased risk for schizophrenia in 350 families with an affected offspring and confirmed association to patient delusion and positive symptom severity. Molecular cloning and cDNA sequencing in human brain revealed that NRG3 undergoes complex splicing, giving rise to multiple structurally distinct isoforms. RNA expression profiling of these isoforms in the prefrontal cortex of 400 individuals revealed that NRG3 expression is developmentally regulated and pathologically increased in schizophrenia. Moreover, we show that rs10748842 lies within a DNA ultraconserved element and homedomain and strongly predicts brain expression of NRG3 isoforms that contain a unique developmentally regulated 5' exon (P = 1.097E(-12) to 1.445E(-15)). Our observations strengthen the evidence that NRG3 is a schizophrenia susceptibility gene, provide quantitative insight into NRG3 transcription traits in the human brain, and reveal a probable mechanistic basis for disease association. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 42 | Neurochem. Int. 2010 Jul 56: 906-10 |
| PMID | 20371257 |
| Title | Neuregulin 1-induced AKT phosphorylation in monozygotic twins discordant for schizophrenia. |
| Abstract | Patients with schizophrenia exhibit decreased neuregulin 1 (NRG1)-stimulated AKT phosphorylation in peripheral lymphoblasts. Here, we examined this peripheral marker in monozygotic twins discordant for schizophrenia and in healthy monozygotic twins without psychiatric disorders. B lymphoblasts were stimulated with NRG1a (65 amino-acid residue recombinant protein from the epidermal growth factor [EGF] domain) for 30min. The protein isolated from the cells was analysed by Western blotting. The dependent measure was the ratio of phosphorylated AKT (pAKT) and total AKT at baseline (without NRG1 stimulation) and after NRG1 stimulation (pAKT/AKT). The results revealed that in the case of the unaffected co-twins of patients with schizophrenia, NRG1-stimulated pAKT/AKT ratio was in between the values of their co-twins with schizophrenia and that of the healthy control twin pairs. When the affected twins with schizophrenia were compared with their unaffected co-twins using a Mann-Whitney U-test, we found significantly lower NRG1-induced pAKT/AKT ratios in the patients relative to their unaffected co-twins (p=0.004). However, using a more conservative analysis (Kruskal-Wallis ANOVA followed tests for multiple comparisons), this difference was not significant. The unaffected co-twins of patients with schizophrenia did not differ significantly from the healthy control twins. In the baseline condition, the pAKT/AKT ratios were similar in all groups. These results indicate that impaired AKT-related intracellular signaling is partly related to the developed illness and cannot fully be explained by the genetic background of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 43 | Toxicol. Appl. Pharmacol. 2010 Jan 242: 209-23 |
| PMID | 19850060 |
| Title | Potent homocysteine-induced ERK phosphorylation in cultured neurons depends on self-sensitization via system Xc(-). |
| Abstract | Homocysteine is increased during pathological conditions, endangering vascular and cognitive functions, and elevated homocysteine during pregnancy may be correlated with an increased incidence of schizophrenia in the offspring. This study showed that millimolar homocysteine concentrations in saline medium cause phosphorylation of extracellular-signal regulated kinases 1 and 2 (ERK(1/2)) in cerebellar granule neurons, inhibitable by metabotropic but not ionotropic glutamate receptor antagonists. These findings are analogous to observations by Zieminska et al. (2003), that similar concentrations cause neuronal death. However, these concentrations are much higher than those occurring clinically during hyperhomocysteinemia. It is therefore important that a approximately 10-fold increase in potency occurred in the presence of the glutamate precursor glutamine, when ERK(1/2) phosphorylation became inhibitable by NMDA or non-NMDA antagonists and dependent upon epidermal growth factor (EGF) receptor transactivation. However, glutamate release to the medium was reduced, suggesting that reversal of the cystine/glutamate antiporter, system X(c)(-) could be involved in potentiation of the response by causing a localized release of initially accumulated homocysteine. In agreement with this hypothesis further enhancement of ERK(1/2) phosphorylation occurred in the additional presence of cystine. Pharmacological inhibition of system X(c)(-) prevented the effect of micromolar homocysteine concentrations, and U0126-mediated inhibition of ERK(1/2) phosphorylation enhanced homocysteine-induced death. In conclusion, homocysteine interacts with system X(c)(-) like quisqualate (Venkatraman et al. 1994), by "self-sensitization" with initial accumulation and subsequent release in exchange with cystine and/or glutamate, establishing high local homocysteine concentrations, which activate adjacent ionotropic glutamate receptors and cause neurotoxicity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 44 | Biosci. Rep. 2010 Aug 30: 267-75 |
| PMID | 19681757 |
| Title | In silico analysis of neuregulin 1 evolution in vertebrates. |
| Abstract | NRG1 (neuregulin 1) belongs to the NRG family of EGF (epidermal growth factor)-like signalling molecules involved in cell-cell communication during development and disease. It plays important roles in the developing tissues of the nerves, heart and mammary glands. Particularly in neurobiology, NRG1 signalling is associated with synaptic transmission, myelination of Schwann cells and the human disease of schizophrenia. Many different isoforms of NRG1 make the molecule highly sophisticated in biological activities and a great diversity of in vivo functions. The nervous system is a common trait in all bilateria (higher animals), but based on the BLAST information from the currently available databases it appears that NRG1 orthologues can only be identified in vertebrates. The gene was analysed in silico for type I-IV CDSs (coding sequences) from ten vertebrate genomes. The gene loci, structures of coding-intronic sequences, ClustalW program analyses, phylogenetic trees and conserved motifs in ecto- and cyto-plasmic domains were analysed and compared. Here, we conclude that non-mammalian vertebrates mainly carry type I (may have evolved a spacer different from mammalian isoforms), II and III NRG1s. The type IV NRG1 N-terminal CDSs can be identified from most of the mammalian genomes studied; however, the corresponding rodent sequences lack the start codon. The evolutionary conservation of a CDS59-CDS24-CDS103 domain, intracellular phosphorylation sites and bipartite nuclear localization signals is of physiological significance. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 45 | Nihon Shinkei Seishin Yakurigaku Zasshi 2011 Nov 31: 209-15 |
| PMID | 22256609 |
| Title | [Vulnerability of dopamine circuit development to cytokines from the periphery: implication in schizophrenia]. |
| Abstract | Epidermal growth factor (EGF) and neuregulin-1 (NRG) belong to the ErbB ligand family and both exert neurotrophic actions on midbrain dopamine neurons. According to the immune inflammatory hypothesis for schizophrenia, we have established rodent models for this illness by exposing their neonates to these cytokines. At post-pubertal stage, these animals develop various neurobehavioral abnormalities such as prepulse inhibition (PPI) and social interaction deficits. In this review, we introduce neurochemical features of the EGF-treated rats and NRG-treated mice, which exhibit persistent increases in tyrosine hydroxylase levels and dopamine release in the globus pallidus and prelimbic cortex (medial prefrontal cortex), respectively. Local blockade of the hyperdopaminergic state in EGF-treated rats ameliorates their behavioral deficits. These findings suggest that development of the midbrain dopamine system is vulnerable to circulating cytokines at perinatal and/or prenatal stages and potentially influences schizophrenia risk or neuropathology. The dopamine hypothesis for schizophrenia is re-evaluated with the obtained results as well as with published literatures in this review. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 46 | Structure 2011 Jun 19: 779-89 |
| PMID | 21620716 |
| Title | The structure of neurexin 1? reveals features promoting a role as synaptic organizer. |
| Abstract | ?-neurexins are essential synaptic adhesion molecules implicated in autism spectrum disorder and schizophrenia. The ?-neurexin extracellular domain consists of six LNS domains interspersed by three EGF-like repeats and interacts with many different proteins in the synaptic cleft. To understand how ?-neurexins might function as synaptic organizers, we solved the structure of the neurexin 1? extracellular domain (n1?) to 2.65 Å. The L-shaped molecule can be divided into a flexible repeat I (LNS1-EGF-A-LNS2), a rigid horseshoe-shaped repeat II (LNS3-EGF-B-LNS4) with structural similarity to so-called reelin repeats, and an extended repeat III (LNS5-EGF-B-LNS6) with controlled flexibility. A 2.95 Å structure of n1? carrying splice insert SS#3 in LNS4 reveals that SS#3 protrudes as a loop and does not alter the rigid arrangement of repeat II. The global architecture imposed by conserved structural features enables ?-neurexins to recruit and organize proteins in distinct and variable ways, influenced by splicing, thereby promoting synaptic function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 47 | J. Biol. Chem. 2011 Jul 286: 24350-63 |
| PMID | 21572038 |
| Title | Transautocrine signaling by membrane neuregulins requires cell surface targeting, which is controlled by multiple domains. |
| Abstract | The neuregulins (NRGs) play important roles in animal development and homeostasis, and their deregulation has been linked to diseases such as cancer and schizophrenia. The NRGs belong to the epidermal growth factor (EGF) family of transmembrane growth factors. Although NRGs may be synthesized as transmembrane proteins (the pro-NRGs), some of them lack an N-terminal signal sequence, raising the question of how these pro-NRGs are directed to the plasma membrane. Here we have explored the domains of pro-NRGs that are required for their membrane anchoring, cell surface exposure, and biological activity. We show that an internal hydrophobic region acts as a membrane-anchoring domain, but other regions of pro-NRG are required for proper sorting to the plasma membrane. Using mutants that are located in different subcellular compartments, we show that only plasma membrane-exposed pro-NRG is biologically active. At this location, the pro-NRGs may act as transautocrine molecules (i.e. as membrane factors able to activate receptors present in cells that are in physical contact with the pro-NRG-producing cells (in trans) or capable of activating receptors present in the pro-NRG-producing cells (in cis)). |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 48 | PLoS ONE 2011 -1 6: e25831 |
| PMID | 22022452 |
| Title | Pallidal hyperdopaminergic innervation underlying D2 receptor-dependent behavioral deficits in the schizophrenia animal model established by EGF. |
| Abstract | Epidermal growth factor (EGF) is one of the ErbB receptor ligands implicated in schizophrenia neuropathology as well as in dopaminergic development. Based on the immune inflammatory hypothesis for schizophrenia, neonatal rats are exposed to this cytokine and later develop neurobehavioral abnormality such as prepulse inhibition (PPI) deficit. Here we found that the EGF-treated rats exhibited persistent increases in tyrosine hydroxylase levels and dopamine content in the globus pallidus. Furthermore, pallidal dopamine release was elevated in EGF-treated rats, but normalized by subchronic treatment with risperidone concomitant with amelioration of their PPI deficits. To evaluate pathophysiologic roles of the dopamine abnormality, we administered reserpine bilaterally to the globus pallidus to reduce the local dopamine pool. Reserpine infusion ameliorated PPI deficits of EGF-treated rats without apparent aversive effects on locomotor activity in these rats. We also administered dopamine D1-like and D2-like receptor antagonists (SCH23390 and raclopride) and a D2-like receptor agonist (quinpirole) to the globus pallidus and measured PPI and bar-hang latencies. Raclopride (0.5 and 2.0 µg/site) significantly elevated PPI levels of EGF-treated rats, but SCH23390 (0.5 and 2.0 µg/site) had no effect. The higher dose of raclopride induced catalepsy-like changes in control animals but not in EGF-treated rats. Conversely, local quinpirole administration to EGF-untreated control rats induced PPI deficits and anti-cataleptic behaviors, confirming the pathophysiologic role of the pallidal hyperdopaminergic state. These findings suggest that the pallidal dopaminergic innervation is vulnerable to circulating EGF at perinatal and/or neonatal stages and has strong impact on the D2-like receptor-dependent behavioral deficits relevant to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 49 | Curr Alzheimer Res 2011 May -1: -1 |
| PMID | 21605034 |
| Title | BACE1 Dependent Neuregulin Proteolysis. |
| Abstract | Neuregulin-1 (NRG1), which is also called acetylcholine receptor inducing activity (ARIA) or glial growth factor (GGF), signals as a ligand of ErbB receptors in a variety of important developmental processes but also later in life. NRG1 mediated signaling is crucial for cardiogenesis and the development of the breast. In the nervous system, NRG1 functions are essential for peripheral myelination, the establishment and maintenance of neuromuscular and sensorimotoric systems as well as for the plasticity of cortical neuronal circuits. There is strong evidence that deregulation of NRG1 is involved in breast cancer and schizophrenia. Many splice variants of NRG1 are expressed in the brain and all contain an EGF-like domain, which exerts the NRG1 function by limited proteolysis from its membrane bound precursor protein. In addition, most NRG1 isoforms contain a transmembrane domain, which is processed by ?-secretase after shedding. ?-Secretase (?-site amyloid precursor protein cleaving enzyme 1; BACE1) has been identified based on its role as the rate limiting enzyme of amyloid-?-peptide (A?) production. A? is the major component of amyloid plaques in Alzheimer`s disease (AD). More recently it was shown that Neuregulin-1 activity is highly dependent on the cleavage by BACE1 during early postnatal development. In BACE1 KO mice a role for BACE1 dependent proteolysis of NRG1 in the process of peripheral myelination could be demonstrated. Here we summarize the current knowledge about the role of NRG1 proteolysis for ErbB receptor mediated signaling during development and in Alzheimer`s disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 50 | J. Neurochem. 2011 Jul 118: 45-56 |
| PMID | 21517852 |
| Title | Qualitative and quantitative re-evaluation of epidermal growth factor-ErbB1 action on developing midbrain dopaminergic neurons in vivo and in vitro: target-derived neurotrophic signaling (Part 1). |
| Abstract | Although epidermal growth factor (EGF) receptor (ErbB1) is implicated in Parkinson's disease and schizophrenia, the neurotrophic action of ErbB1 ligands on nigral dopaminergic neurons remains controversial. Here, we ascertained colocalization of ErbB1 and tyrosine hydroxylase (TH) immunoreactivity and then characterized the neurotrophic effects of ErbB1 ligands on this cell population. In mesencephalic culture, EGF and glial-derived neurotrophic factor (GDNF) similarly promoted survival and neurite elongation of dopaminergic neurons and dopamine uptake. The EGF-promoted dopamine uptake was not inhibited by GDNF-neutralizing antibody or TrkB-Fc, whereas EGF-neutralizing antibody fully blocked the neurotrophic activity of the conditioned medium that was prepared from EGF-stimulated mesencephalic cultures. The neurotrophic action of EGF was abolished by ErbB1 inhibitors and genetic disruption of erbB1 in culture. In vivo administration of ErbB1 inhibitors to rat neonates diminished TH and dopamine transporter (DAT) levels in the striatum and globus pallidus but not in the frontal cortex. In parallel, there was a reduction in the density of dopaminergic varicosities exhibiting intense TH immunoreactivity. In agreement, postnatal erbB1-deficient mice exhibited similar decreases in TH levels. Although neurotrophic supports to dopaminergic neurons are redundant, these results confirm that ErbB1 ligands contribute to the phenotypic and functional development of nigral dopaminergic neurons. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 51 | J. Biol. Chem. 2011 May 286: 18434-43 |
| PMID | 21471224 |
| Title | Alpha1,6-fucosyltransferase-deficient mice exhibit multiple behavioral abnormalities associated with a schizophrenia-like phenotype: importance of the balance between the dopamine and serotonin systems. |
| Abstract | Previously, we reported that ?1,6-fucosyltransferase (Fut8)-deficient (Fut8(-/-)) mice exhibit emphysema-like changes in the lung and severe growth retardation due to dysregulation of TGF-?1 and EGF receptors and to abnormal integrin activation, respectively. To study the role of ?1,6-fucosylation in brain tissue where Fut8 is highly expressed, we examined Fut8(-/-) mice using a combination of neurological and behavioral tests. Fut8(-/-) mice exhibited multiple behavioral abnormalities consistent with a schizophrenia-like phenotype. Fut8(-/-) mice displayed increased locomotion compared with wild-type (Fut8(+/+)) and heterozygous (Fut8(+/-)) mice. In particular, Fut8(-/-) mice showed strenuous hopping behavior in a novel environment. Working memory performance was impaired in Fut8(-/-) mice as evidenced by the Y-maze tests. Furthermore, Fut8(-/-) mice showed prepulse inhibition (PPI) deficiency. Intriguingly, although there was no significant difference between Fut8(+/+) and Fut8(+/-) mice in the PPI test under normal conditions, Fut8(+/-) mice showed impaired PPI after exposure to a restraint stress. This result suggests that reduced expression of Fut8 is a plausible cause of schizophrenia and related disorders. The levels of serotonin metabolites were significantly decreased in both the striatum and nucleus accumbens of the Fut8(-/-) mice. Likewise, treatment with haloperidol, which is an antipsychotic drug that antagonizes dopaminergic and serotonergic receptors, significantly reduced hopping behaviors. The present study is the first to clearly demonstrate that ?1,6-fucosylation plays an important role in the brain, and that it might be related to schizophrenia-like behaviors. Thus, the results of the present study provide new insights into the underlying mechanisms responsible for schizophrenia and related disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 52 | Bull. Math. Biol. 2012 Mar 74: 717-35 |
| PMID | 22147103 |
| Title | A model of neuregulin control of NMDA receptors on synaptic spines. |
| Abstract | Neuregulin (Nrg) through its receptor ErbB4 modulates the activity of the N-Methyl-D-Aspartate (NMDA) receptor (NMDAR) at synapses. As modification of this pathway has been implicated in schizophrenia, it is of great interest to define it in precise quantitative terms. Kinetic models of the epidermal growth factor (EGF)/ErbB receptor signalling pathway describing activation, desensitization, and tyrosine phosphorylation of EGFR/ErbB followed by binding and activation of Src family kinases that is subsequently followed by phosphorylation of target proteins are available. We have adapted these to give a kinetic description of NMDAR modulation by Nrg that recapitulates the observed kinetics of autophosphorylation of the ErbB dimer as well as the modulation of the NMDAR by Src kinase, according to whether the kinases are activated or deactivated. This quantitative description of the Nrg/NMDAR pathway provides a model for experimental elucidation of what goes awry in animal models of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 53 | Proc. Natl. Acad. Sci. U.S.A. 2012 Aug 109: 13984-9 |
| PMID | 22891299 |
| Title | Dynamically varying interactions between heregulin and ErbB proteins detected by single-molecule analysis in living cells. |
| Abstract | Heregulin (HRG) belongs to the family of EGFs and activates the receptor proteins ErbB3 and ErbB4 in a variety of cell types to regulate cell fate. The interactions between HRG and ErbB3/B4 are important to the pathological mechanisms underlying schizophrenia and some cancers. Here, we observed the reaction kinetics between fluorescently labeled single HRG molecules and ErbB3/B4 on the surfaces of MCF-7 human breast cancer cells. The equilibrium association and the dissociation from equilibrium were also measured using single-molecule imaging techniques. The unitary association processes mirrored the EGF and ErbB1 interactions in HeLa cells [Teramura Y, et al. (2006) EMBO J 25:4215-4222], suggesting that the predimerization of the receptors, followed by intermediate formation (between the first and second ligand-binding events to a receptor dimer), accelerated the formation of doubly liganded signaling dimers of the receptor molecules. However, the dissociation analysis suggested that the first HRG dissociation from the doubly liganded dimer was rapid, but the second dissociation from the singly liganded dimer was slow. The dissociation rate constant from the liganded monomer was intermediate. The dynamic changes in the association and dissociation kinetics in relation to the dimerization of ErbB displayed negative cooperativity, which resulted in apparent low- and high-affinity sites of HRG association on the cell surface. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 54 | Curr Alzheimer Res 2012 Feb 9: 178-83 |
| PMID | 22455478 |
| Title | BACE1 dependent neuregulin processing: review. |
| Abstract | Neuregulin-1 (NRG1), known also as heregulin, acetylcholine receptor inducing activity (ARIA), glial growth factor (GGF), or sensory and motor neuron derived factor (SMDF), plays essential roles in several developmental processes, and is required also later in life. Many variants of NRG1 are produced via alternative splicing and usage of distinct promoters. All contain an epidermal growth factor (EGF)-like domain, which alone is sufficient to bind and activate the cognate receptors, members of the ErbB family. NRG1 mediated signaling is crucial for cardiogenesis and the development of the mammary gland and ErbB2 (HER2), an orphan co-receptor for NRG1 is the target of the drug Herceptin? (trastuzumab) used for treatment of metastatic breast cancer. In the nervous system, NRG1 controls the early development of subpopulations of neural crest cells. In particular, NRG1 acts as an essential paracrine signaling molecule expressed on the axonal surface, where it signals to Schwann cells throughout development and regulates the thickness of the myelin sheath. NRG1 is required also by other cell types in the nervous system, for instance as an axonal signal released by proprioceptive afferents to induce development of the muscle spindle, and it controls aspects of cortical interneuron development as well as the formation of thalamocortical projections. Work from several laboratories implicates dysregulation of NRG1/ErbB4 signaling in the etiology of schizophrenia. Biochemical studies have shown that the precursor proteins of NRG1 can be released from the membrane through limited proteolysis. In addition, most NRG1 isoforms contain a transmembrane domain, which is processed by ?-secretase after shedding. Thereby the intracellular domain is released into the cytoplasm. Despite this, the importance of NRG1 cleavage for its functions in vivo remained unclear until recently. ?- Secretase (?-site amyloid precursor protein cleaving enzyme 1, BACE1) was first identified through its function as the rate limiting enzyme of amyloid-?-peptide (A?) production. A? is the major component of amyloid plaques in Alzheimer's disease (AD). More recently it was shown that Neuregulin-1 is a major physiological substrate of BACE1 during early postnatal development. Mutant mice lacking BACE1 display severe hypomyelination of peripheral nerves similar to that seen in mice lacking NRG1/ErbB signaling in Schwann cells, and a BACE1-dependent activation of NRG1 in the process of peripheral myelination was proposed. Here we summarize the current knowledge about the role of NRG1 proteolysis for ErbB receptor mediated signaling during development and in Alzheimer's disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 55 | Int. J. Neuropsychopharmacol. 2012 Sep 15: 1149-60 |
| PMID | 21943960 |
| Title | Clozapine induction of ERK1/2 cell signalling via the EGF receptor in mouse prefrontal cortex and striatum is distinct from other antipsychotic drugs. |
| Abstract | Treatment resistance remains a major obstacle in schizophrenia, with antipsychotic drugs (APDs) being ineffective in about one third of cases. Poor response to standard therapy leaves the APD clozapine as the only effective treatment for many patients. The reason for the superior efficacy of clozapine is unknown, but as we have proposed previously it may involve modulation of neuroplasticity and connectivity through induction of interconnected mitogenic signalling pathways. These include the mitogen-activated protein kinase-extracellular signal regulated kinase (MAPK-ERK) cascade and epidermal growth factor (EGF)/ErbB systems. Clozapine, distinct from other APDs, induced initial inhibition and subsequent activation of the ERK response in prefrontal cortical (PFC) neurons in vitro and in vivo, an action mediated by the EGF receptor (ErbB1). Here we examine additionally the striatum of C57Bl/6 mice to determine if clozapine, olanzapine, and haloperidol differentially regulate the ERK1/2 pathway in a region or time-specific manner conditional on the EGF receptor. Following acute treatment, only clozapine caused delayed striatal ERK phosphorylation through EGF receptor phosphorylation (tyrosine 1068 site) and MEK that paralleled cortical ERK phosphorylation. Olanzapine induced initial pERK1-specific blockade and an elevation 24-h later in PFC but had no effect in the striatum. By contrast, haloperidol significantly stimulated pERK1 in striatum for up to 8 h, but exerted limited effect in PFC. Clozapine but not olanzapine or haloperidol recruited the EGF receptor to signal to ERK. These in-vivo data reinforce our previous findings that clozapine's action may be uniquely linked to the EGF signalling system, potentially contributing to its distinctive clinical profile. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 56 | CNS Neurosci Ther 2013 Feb 19: 136-7 |
| PMID | 23339361 |
| Title | Concerning HB-EGF brain levels in schizophrenia: cellular distribution of putative sheddases may matter. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 57 | Cell. Signal. 2013 Oct 25: 2060-8 |
| PMID | 23770287 |
| Title | Rit subfamily small GTPases: regulators in neuronal differentiation and survival. |
| Abstract | Ras family small GTPases serve as binary molecular switches to regulate a broad array of cellular signaling cascades, playing essential roles in a vast range of normal physiological processes, with dysregulation of numerous Ras-superfamily G-protein-dependent regulatory cascades underlying the development of human disease. However, the physiological function for many "orphan" Ras-related GTPases remain poorly characterized, including members of the Rit subfamily GTPases. Rit is the founding member of a novel branch of the Ras subfamily, sharing close homology with the neuronally expressed Rin and Drosophila Ric GTPases. Here, we highlight recent studies using transgenic and knockout animal models which have begun to elucidate the physiological roles for the Rit subfamily, including emerging roles in the regulation of neuronal morphology and cellular survival signaling, and discuss new genetic data implicating Rit and Rin signaling in disorders such as cancer, Parkinson's disease, autism, and schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 58 | Front Cell Neurosci 2013 -1 7: 4 |
| PMID | 23408472 |
| Title | ErbB1-4-dependent EGF/neuregulin signals and their cross talk in the central nervous system: pathological implications in schizophrenia and Parkinson's disease. |
| Abstract | Ligands for ErbB1-4 receptor tyrosine kinases, such as epidermal growth factor (EGF) and neuregulins, regulate brain development and function. Thus, abnormalities in their signaling are implicated in the etiology or pathology of schizophrenia and Parkinson's disease. Among the ErbB receptors, ErbB1, and ErbB4 are expressed in dopamine and GABA neurons, while ErbB1, 2, and/or 3 are mainly present in oligodendrocytes, astrocytes, and their precursors. Thus, deficits in ErbB signaling might contribute to the neurological and psychiatric diseases stemming from these cell types. By incorporating the latest cancer molecular biology as well as our recent progress, we discuss signal cross talk between the ErbB1-4 subunits and their neurobiological functions in each cell type. The potential contribution of virus-derived cytokines (virokines) that mimic EGF and neuregulin-1 in brain diseases are also discussed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 59 | Neuroscience 2013 Sep 248: 670-80 |
| PMID | 23811072 |
| Title | A neuregulin 1 transmembrane domain mutation causes imbalanced glutamatergic and dopaminergic receptor expression in mice. |
| Abstract | The neuregulin 1 gene has repeatedly been identified as a susceptibility gene for schizophrenia, thus mice with genetic mutations in this gene offer a valuable tool for studying the role of neuregulin 1 in schizophrenia-related neurotransmission. In this study, slide-based receptor autoradiography was used to quantify glutamatergic N-methyl-d-aspartate (NMDA), dopaminergic D2, cannabinoid CB1 and acetylcholine M1/4 receptor levels in the brains of male heterozygous transmembrane domain neuregulin 1 mutant (Nrg1(+/-)) mice at two ages. Mutant mice expressed small but significant increases in NMDA receptor levels in the cingulate cortex (7%, p=0.044), sensory cortex (8%, p=0.024), and motor cortex (8%, p=0.047), effects that were independent of age. In the nucleus accumbens and thalamus Nrg1(+/-) mice exhibited age-dependent alterations in NMDA receptors. Nrg1(+/-) mice showed a statistically significant increase in NMDA receptor levels in the nucleus accumbens of 14-week-old Nrg1(+/-) mice compared to control littermates of the same age (12%, p=0.026), an effect that was not seen in 20-week-old mice. In contrast, NMDA receptor levels in the thalamus, while initially unchanged in 14-week-old mice, were then decreased in the 20-week-old Nrg1(+/-) mice compared to control littermates of the same age (14%, p=0.011). Nrg1(+/-) mutant mice expressed a significant reduction in D2 receptor levels (13-16%) in the striatum compared to controls, independent of age. While there was a borderline significant increase (6%, p=0.058) in cannabinoid CB1 receptor levels in the substantia nigra of Nrg1(+/-) mice compared to controls, CB1 as well as acetylcholine M1/4 receptors showed no change in Nrg1(+/-) mice in any other brain region examined. These data indicate that a Nrg1 transmembrane mutation produces selective imbalances in glutamatergic and dopaminergic neurotransmission, which are two key systems believed to contribute to schizophrenia pathogenesis. While the effects on these systems are subtle, they may underlie the susceptibility of these mutants to further impacts. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 60 | Neurosci. Lett. 2013 Jun 547: 21-5 |
| PMID | 23669645 |
| Title | Neurobehavioral deficits of epidermal growth factor-overexpressing transgenic mice: impact on dopamine metabolism. |
| Abstract | Epidermal growth factor (EGF) and its family member neuregulin-1 are implicated in the etiology of schizophrenia. Our recent pharmacological studies indicate that EGF injections to neonatal and adult rats both induce neurobehavioral deficits relevant to schizophrenia. We, however, did not evaluate the genetic impact of EGF transgene on neurobehavioral traits. Here we analyzed transgenic mice carrying the transgene of mouse EGF cDNA. As compared to control littermates, heterozygous EGF transgenic mice had an increase in EGF mRNA levels and showed significant decreases in prepulse inhibition and context-dependent fear learning, but there were no changes in locomotor behaviors and sound startle responses. In addition, these transgenic mice exhibited higher behavioral sensitivity to the repeated cocaine injections. There were neurochemical alterations in metabolic enzymes of dopamine (i.e., tyrosine hydroxylase, dopa decarboxylase, catechol-O-methyl transferase) and monoamine contents in various brain regions of the EGF transgenic mice, but there were no apparent neuropathological signs in the brain. The present findings rule out the indirect influence of anti-EGF antibody production on the reported behavioral deficits of EGF-injected mice. These results support the argument that aberrant hyper-signals of EGF have significant impact on mouse behavioral traits and dopamine metabolism. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 61 | Transl Psychiatry 2013 -1 3: e252 |
| PMID | 23632456 |
| Title | ErbB inhibitors ameliorate behavioral impairments of an animal model for schizophrenia: implication of their dopamine-modulatory actions. |
| Abstract | Ligands for ErbB receptors, including epidermal growth factor (EGF) and neuregulin-1, have a neurotrophic activity on midbrain dopaminergic neurons and are implicated in the pathophysiology of schizophrenia. Although ErbB kinase inhibitors ameliorate behavioral deficits of the schizophrenia model that was established by hippocampal lesioning of rat pups, the antipsychotic action of ErbB kinase inhibitors and its general applicability to other models are not fully characterized. Using a different animal model, here, we examined whether and how ErbB kinase inhibitors ameliorate the behavioral endophenotypes relevant to schizophrenia. The animal model for schizophrenia was prepared by exposing neonatal rats to the cytokine EGF. Intraventricular infusion of the ErbB1 inhibitors ZD1839 and PD153035 in these animals ameliorated the deficits in startle response and prepulse inhibition in a dose-dependent manner. The deficits of latent inhibition of fear learning were also alleviated by ZD1839 with its limited effects on body weight gain or locomotor activity. ZD1839 infusion also decreased the busting activity of nigral dopamine (DA) neurons and reduced pallidal DA metabolism, a result that mimics the anti-dopaminergic profile of risperidone and haloperidol in this brain region. ErbB inhibitors appear to have anti-dopaminergic actions to alleviate some of the behavioral deficits common to animal models for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 62 | J. Neurochem. 2013 Aug 126: 518-28 |
| PMID | 23437767 |
| Title | Exposure to the cytokine EGF leads to abnormal hyperactivity of pallidal GABA neurons: implications for schizophrenia and its modeling. |
| Abstract | Previous studies on a cytokine model for schizophrenia reveal that the hyperdopaminergic innervation and neurotransmission in the globus pallidus (GP) is involved in its behavioral impairments. Here, we further explored the physiological consequences of the GP abnormality in the indirect pathway, using the same schizophrenia model established by perinatal exposure to epidermal growth factor (EGF). Single-unit recordings revealed that the neural activity from the lateral GP was elevated in EGF-treated rats in vivo and in vitro (i.e., slice preparations), whereas the central area of the GP exhibited no significant differences. The increase in the pallidal activity was normalized by subchronic treatment with risperidone, which is known to ameliorate their behavioral deficits. We also monitored extracellular GABA concentrations in the substantia nigra, one of the targets of pallidal efferents. There was a significant increase in basal GABA levels in EGF-treated rats, whereas high potassium-evoked GABA effluxes and glutamate levels were not affected. A neurotoxic lesion in the GP of EGF-treated rats normalized GABA concentrations to control levels. Corroborating our in vivo results, GABA release from GP slices was elevated in EGF-treated animals. These findings suggest that the hyperactivity and enhanced GABA release of GP neurons represent the key pathophysiological features of this cytokine-exposure model for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 63 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2013 Jan 40: 353-63 |
| PMID | 23142770 |
| Title | Clozapine regulation of p90RSK and c-Fos signaling via the ErbB1-ERK pathway is distinct from olanzapine and haloperidol in mouse cortex and striatum. |
| Abstract | Treatment of the positive psychotic symptoms of schizophrenia with standard antipsychotic drugs (APDs) is ineffective in a proportion of cases. For these treatment resistant patients the alternative is the APD clozapine which is superior to other agents but carries serious side effects. Why clozapine is uniquely effective is unknown, but we have previously postulated may involve G-protein coupled receptor (GPCR) and epidermal growth factor (EGF) receptor (ErbB1) transactivation signaling to the mitogen-activated protein kinase-extracellular signal regulated kinase (MAPK-ERK) cascade. This was based upon clozapine induced initial down-regulation and delayed ErbB1 mediated activation of the cortical and striatal ERK response in vivo distinct from other APDs. This study investigated if modulation of the ErbB1-ERK1/2 pathway by clozapine, olanzapine and haloperidol affected expression of the ERK substrates p90RSK and c-Fos, factors that regulate transcription of proteins associated with neuroplasticity and synapse formation in C57Bl/6 mice. In cortex and striatum, acute clozapine treatment induced biphasic p90RSK phosphorylation via MEK that paralleled ERK phosphorylation independent of EGF receptor blockade. By contrast, olanzapine and haloperidol caused p90RSK phosphorylation that was not concomitant with ERK signaling over a 24-hour period. For c-Fos, clozapine elevated expression 24h after administration, a timeframe consistent with ERK activation at 8h. Alternatively, haloperidol stimulation of c-Fos levels limited to the striatum was in accord with direct transcriptional regulation through ERK. The unique spatio-temporal expression of downstream nuclear markers of the ErbB1-ERK pathway invoked by clozapine may contribute to its effectiveness in treatment resistant schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 64 | Brain Behav. Immun. 2013 Jul 31: 90-5 |
| PMID | 22749891 |
| Title | Serum and gene expression profile of cytokines in first-episode psychosis. |
| Abstract | An inflammatory syndrome has been previously reported in chronic schizophrenia. The aims of this study were to investigate: (1) serum levels and leukocyte gene expression of cytokines in patients with first-episode psychosis and controls; and (2) possible causes of abnormal cytokine levels in first-episode psychosis, testing their association with psychosocial stressors, current nicotine and cannabis use, and duration of antipsychotic treatment. We recruited 24 first-episode psychosis patients and 24 healthy controls matched for age, gender, ethnicity and body mass index. Serum interleukin(IL)-1?, IL-1?, IL-2, IL-4, IL-6, IL-8, IL-10, Tumour Necrosis Factor- ? (TNF-?), Interferon- ? (IFN-?), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), and monocyte chemotactic protein-1 (MCP-1) were analysed in all subjects. Leukocyte gene expression analyses were conducted only for those cytokines that were different between-groups in the serum analyses. Patients had significantly higher serum levels of IL-1? (effect size d=0.6, p=0.03), IL-1? (d=0.4, p=0.01), IL-8 (d=0.6, p=0.01) and TNF-? (d=0.7, p=0.05) and a trend for higher IL-6 serum levels (d=0.3, p=0.09) when compared with controls. Leukocyte m-RNA levels of IL-1? (d=0.6, p=0.04), IL-6 (d=0.7, p=0.01) and TNF-? (d=1.6, p<0.001), but not IL-1? and IL-8, were also significantly higher in patients. A history of childhood trauma was associated with higher TNF-? serum levels (p=0.01), while more recent stressful life-events were associated with higher TNF-? mRNA levels in leukocytes (p=0.002). In conclusion, first-episode psychosis is characterised by a pro-inflammatory state supported, at least in part, by activation of leukocytes. Past and recent stressors contribute to this pro-inflammatory state. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 65 | Mol Autism 2014 -1 5: 38 |
| PMID | 25061506 |
| Title | Integrative proteomic analysis of the NMDA NR1 knockdown mouse model reveals effects on central and peripheral pathways associated with schizophrenia and autism spectrum disorders. |
| Abstract | Over the last decade, the transgenic N-methyl-D-aspartate receptor (NMDAR) NR1-knockdown mouse (NR1(neo-/-)) has been investigated as a glutamate hypofunction model for schizophrenia. Recent research has now revealed that the model also recapitulates cognitive and negative symptoms in the continuum of other psychiatric diseases, particularly autism spectrum disorders (ASD). As previous studies have mostly focussed on behavioural readouts, a molecular characterisation of this model will help to identify novel biomarkers or potential drug targets. Here, we have used multiplex immunoassay analyses to investigate peripheral analyte alterations in serum of NR1(neo-/-) mice, as well as a combination of shotgun label-free liquid chromatography mass spectrometry, bioinformatic pathway analyses, and a shotgun-based 40-plex selected reaction monitoring (SRM) assay to investigate altered molecular pathways in the frontal cortex and hippocampus. All findings were cross compared to identify translatable findings between the brain and periphery. Multiplex immunoassay profiling led to identification of 29 analytes that were significantly altered in sera of NR1(neo-/-) mice. The highest magnitude changes were found for neurotrophic factors (VEGFA, EGF, IGF-1), apolipoprotein A1, and fibrinogen. We also found decreased levels of several chemokines. Following this, LC-MS(E) profiling led to identification of 48 significantly changed proteins in the frontal cortex and 41 in the hippocampus. In particular, MARCS, the mitochondrial pyruvate kinase, and CamKII-alpha were affected. Based on the combination of protein set enrichment and bioinformatic pathway analysis, we designed orthogonal SRM-assays which validated the abnormalities of proteins involved in synaptic long-term potentiation, myelination, and the ERK-signalling pathway in both brain regions. In contrast, increased levels of proteins involved in neurotransmitter metabolism and release were found only in the frontal cortex and abnormalities of proteins involved in the purinergic system were found exclusively in the hippocampus. Taken together, this multi-platform profiling study has identified peripheral changes which are potentially linked to central alterations in synaptic plasticity and neuronal function associated with NMDAR-NR1 hypofunction. Therefore, the reported proteomic changes may be useful as translational biomarkers in human and rodent model drug discovery efforts. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 66 | J. Comp. Neurol. 2014 Oct 522: 3351-62 |
| PMID | 24752666 |
| Title | Ablation of ErbB4 from excitatory neurons leads to reduced dendritic spine density in mouse prefrontal cortex. |
| Abstract | Dendritic spine loss is observed in many psychiatric disorders, including schizophrenia, and likely contributes to the altered sense of reality, disruption of working memory, and attention deficits that characterize these disorders. ErbB4, a member of the EGF family of receptor tyrosine kinases, is genetically associated with schizophrenia, suggesting that alterations in ErbB4 function contribute to the disease pathology. Additionally, ErbB4 functions in synaptic plasticity, leading us to hypothesize that disruption of ErbB4 signaling may affect dendritic spine development. We show that dendritic spine density is reduced in the dorsomedial prefrontal cortex of ErbB4 conditional whole-brain knockout mice. We find that ErbB4 localizes to dendritic spines of excitatory neurons in cortical neuronal cultures and is present in synaptic plasma membrane preparations. Finally, we demonstrate that selective ablation of ErbB4 from excitatory neurons leads to a decrease in the proportion of mature spines and an overall reduction in dendritic spine density in the prefrontal cortex of weanling (P21) mice that persists at 2 months of age. These results suggest that ErbB4 signaling in excitatory pyramidal cells is critical for the proper formation and maintenance of dendritic spines in excitatory pyramidal cells. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 67 | Eur Neuropsychopharmacol 2014 Nov 24: 1808-18 |
| PMID | 25451700 |
| Title | Disruption of the ErbB signaling in adolescence increases striatal dopamine levels and affects learning and hedonic-like behavior in the adult mouse. |
| Abstract | The ErbB signaling pathway has been genetically and functionally implicated in schizophrenia. Numerous findings support the dysregulation of Neuregulin (NRG) and epidermal growth factor (EGF) signaling in schizophrenia. However, it is unclear whether alterations of these pathways in the adult brain or during development are involved in the pathophysiology of schizophrenia. Herein we characterized the behavioral profile and molecular changes resulting from pharmacologically blocking the ErbB signaling pathway during a critical period in the development of decision making, planning, judgments, emotions, social cognition and cognitive skills, namely adolescence. We demonstrate that chronic administration of the pan-ErbB kinase inhibitor JNJ-28871063 (JNJ) to adolescent mice elevated striatal dopamine levels and reduced preference for sucrose without affecting locomotor activity and exploratory behavior. In adulthood, adolescent JNJ-treated mice continue to consume less sucrose and needed significantly more correct-response trials to reach the learning criterion during the discrimination phase of the T-maze reversal learning task than their saline-injected controls. In addition, JNJ mice exhibited deficit in reference memory but not in working memory as measured in the radial arm maze. Inhibition of the pathway during adolescence did not affect exploratory behavior and locomotor activity in the open field, social interaction, social memory, and reversal learning in adult mice. Our data suggest that alteration of ErbB signaling during adolescence resulted in changes in the dopaminergic systems that emerge in pathological learning and hedonic behavior in adulthood, and pinpoints the possible role of the pathway in the development of cognitive skills and motivated behavior. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 68 | PLoS ONE 2014 -1 9: e104172 |
| PMID | 25093331 |
| Title | Transient overexposure of neuregulin 3 during early postnatal development impacts selective behaviors in adulthood. |
| Abstract | Neuregulin 3 (NRG3), a specific ligand for ErbB4 and a neuronal-enriched neurotrophin is implicated in the genetic predisposition to a broad spectrum of neurodevelopmental, neurocognitive and neuropsychiatric disorders, including Alzheimer's disease, autism and schizophrenia. Genetic studies in schizophrenia demonstrate that risk variants in NRG3 are associated with cognitive and psychotic symptom severity, accompanied by increased expression of prefrontal cortical NRG3. Despite our expanding knowledge of genetic involvement of NRG3 in neurological disorders, little is known about the neurodevelopmental mechanisms of risk. Here we exploited the fact that a paralog of NRG3, NRG1, readily penetrates the murine blood brain barrier (BBB). In this study we synthesized the bioactive epidermal growth factor (EGF) domain of NRG3, and using previously validated in-vivo peripheral injection methodologies in neonatal mice, demonstrate that NRG3 successfully crosses the BBB, where it activates its receptor ErbB4 and downstream Akt signaling at levels of bioactivity comparable to NRG1. To determine the impact of NRG3 overexpression during one critical developmental window, C57BL/6 male mice were subcutaneously injected daily with NRG1-EGF, NRG3-EGF or vehicle from postnatal days 2-10. Mice were tested in adulthood using a comprehensive battery of behavioral tasks relevant to neurocognitive and psychiatric disorders. In agreement with previous studies, developmental overexposure to NRG1 induced multiple non-CNS mediated peripheral effects as well as severely disrupting performance of prepulse inhibition of the startle response. In contrast, NRG3 had no effect on any peripheral measures investigated or sensorimotor gating. Specifically, developmental NRG3 overexposure produced an anxiogenic-like phenotype and deficits in social behavior in adulthood. These results provide primary data to support a role for NRG3 in brain development and function, which appears to be distinct from its paralog NRG1. Furthermore we demonstrate how perturbations in NRG3 expression at distinct developmental stages may contribute to the neurological deficits observed in brain disorders such as schizophrenia and autism. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 69 | Biomed Res Int 2014 -1 2014: 697935 |
| PMID | 24949465 |
| Title | Neuropathologic implication of peripheral neuregulin-1 and EGF signals in dopaminergic dysfunction and behavioral deficits relevant to schizophrenia: their target cells and time window. |
| Abstract | Neuregulin-1 and epidermal growth factor (EGF) are implicated in the pathogenesis of schizophrenia. To test the developmental hypothesis for schizophrenia, we administered these factors to rodent pups, juveniles, and adults and characterized neurobiological and behavioral consequences. These factors were also provided from their transgenes or infused into the adult brain. Here we summarize previous results from these experiments and discuss those from neuropathological aspects. In the neonatal stage but not the juvenile and adult stages, subcutaneously injected factors penetrated the blood-brain barrier and acted on brain neurons, which later resulted in persistent behavioral and dopaminergic impairments associated with schizophrenia. Neonatally EGF-treated animals exhibited persistent hyperdopaminergic abnormalities in the nigro-pallido-striatal system while neuregulin-1 treatment resulted in dopaminergic deficits in the corticolimbic dopamine system. Effects on GABAergic and glutamatergic systems were transient or limited. Even in the adult stage, intracerebral administration and transgenic expression of these factors produced similar but not identical behavioral impairments, although the effects of intracerebral administration were reversible. These findings suggest that dopaminergic development is highly vulnerable to circulating ErbB ligands in the pre- and perinatal stages. Once maldevelopment of the dopaminergic system is established during early development, dopamine-associating behavioral deficits become irreversible and manifest at postpubertal stages. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 70 | Proc. Natl. Acad. Sci. U.S.A. 2014 Apr 111: E1291-9 |
| PMID | 24639501 |
| Title | Cartography of neurexin alternative splicing mapped by single-molecule long-read mRNA sequencing. |
| Abstract | Neurexins are evolutionarily conserved presynaptic cell-adhesion molecules that are essential for normal synapse formation and synaptic transmission. Indirect evidence has indicated that extensive alternative splicing of neurexin mRNAs may produce hundreds if not thousands of neurexin isoforms, but no direct evidence for such diversity has been available. Here we use unbiased long-read sequencing of full-length neurexin (Nrxn)1?, Nrxn1?, Nrxn2?, Nrxn3?, and Nrxn3? mRNAs to systematically assess how many sites of alternative splicing are used in neurexins with a significant frequency, and whether alternative splicing events at these sites are independent of each other. In sequencing more than 25,000 full-length mRNAs, we identified a novel, abundantly used alternatively spliced exon of Nrxn1? and Nrxn3? (referred to as alternatively spliced sequence 6) that encodes a 9-residue insertion in the flexible hinge region between the fifth LNS (laminin-?, neurexin, sex hormone-binding globulin) domain and the third EGF-like sequence. In addition, we observed several larger-scale events of alternative splicing that deleted multiple domains and were much less frequent than the canonical six sites of alternative splicing in neurexins. All of the six canonical events of alternative splicing appear to be independent of each other, suggesting that neurexins may exhibit an even larger isoform diversity than previously envisioned and comprise thousands of variants. Our data are consistent with the notion that ?-neurexins represent extracellular protein-interaction scaffolds in which different LNS and EGF domains mediate distinct interactions that affect diverse functions and are independently regulated by independent events of alternative splicing. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 71 | BMC Neurosci 2014 -1 15: 30 |
| PMID | 24552586 |
| Title | Quetiapine and aripiprazole signal differently to ERK, p90RSK and c-Fos in mouse frontal cortex and striatum: role of the EGF receptor. |
| Abstract | Signaling pathways outside dopamine D2 receptor antagonism may govern the variable clinical profile of antipsychotic drugs (APD) in schizophrenia. One postulated mechanism causal to APD action may regulate synaptic plasticity and neuronal connectivity via the extracellular signal-regulated kinase (ERK) cascade that links G-protein coupled receptors (GPCR) and ErbB growth factor signaling, systems disturbed in schizophrenia. This was based upon our finding that the low D2 receptor affinity APD clozapine induced initial down-regulation and delayed epidermal growth factor receptor (EGFR or ErbB1) mediated activation of the cortical and striatal ERK response in vivo distinct from olanzapine or haloperidol. Here we map whether the second generation atypical APDs aripiprazole and quetiapine affect the EGFR-ERK pathway and its substrates p90RSK and c-Fos in mouse brain, given their divergent agonist and antagonist properties on dopaminergic transmission, respectively. In prefrontal cortex, aripiprazole triggered triphasic ERK phosphorylation that was EGFR-independent but had no significant effect in striatum. Conversely quetiapine did not alter cortical ERK signaling but elevated striatal ERK levels in an EGFR-dependent manner. Induction of ERK by aripiprazole did not affect p90RSK signaling but quetiapine decreased RSK phosphorylation within 1-hour of administration. The transcription factor c-Fos by comparison was a direct target of ERK phosphorylation induced by aripiprazole in cortex and quetiapine in striatum with protein levels in temporal alignment with that of ERK. These data indicate that aripiprazole and quetiapine signal to specific nuclear targets of ERK, which for quetiapine occurs via an EGFR-linked mechanism, possibly indicating involvement of this system in its action. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 72 | PLoS ONE 2015 -1 10: e0124114 |
| PMID | 25992564 |
| Title | Neuregulin 1 expression and electrophysiological abnormalities in the Neuregulin 1 transmembrane domain heterozygous mutant mouse. |
| Abstract | The Neuregulin 1 transmembrane domain heterozygous mutant (Nrg1 TM HET) mouse is used to investigate the role of Nrg1 in brain function and schizophrenia-like behavioural phenotypes. However, the molecular alterations in brain Nrg1 expression that underpin the behavioural observations have been assumed, but not directly determined. Here we comprehensively characterise mRNA Nrg1 transcripts throughout development of the Nrg1 TM HET mouse. In addition, we investigate the regulation of high-frequency (gamma) electrophysiological oscillations in this mutant mouse to associate molecular changes in Nrg1 with a schizophrenia-relevant neurophysiological profile. Using exonic probes spanning the cysteine-rich, epidermal growth factor (EGF)-like, transmembrane and intracellular domain encoding regions of Nrg1, mRNA levels were measured using qPCR in hippocampus and frontal cortex from male and female Nrg1 TM HET and wild type-like (WT) mice throughout development. We also performed electrophysiological recordings in adult mice and analysed gamma oscillatory at baseline, in responses to auditory stimuli and to ketamine. In both hippocampus and cortex, Nrg1 TM HET mice show significantly reduced expression of the exon encoding the transmembrane domain of Nrg1 compared with WT, but unaltered mRNA expression encoding the extracellular bioactive EGF-like and the cysteine-rich (type III) domains, and development-specific and region-specific reductions in the mRNA encoding the intracellular domain. Hippocampal Nrg1 protein expression was not altered, but NMDA receptor NR2B subunit phosphorylation was lower in Nrg1 TM HET mice. We identified elevated ongoing and reduced sensory-evoked gamma power in Nrg1 TM HET mice. We found no evidence to support the claim that the Nrg1 TM HET mouse represents a simple haploinsufficient model. Further research is required to explore the possibility that mutation results in a gain of Nrg1 function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 73 | Curr. Mol. Med. 2015 -1 15: 222-36 |
| PMID | 25817857 |
| Title | Neurobehavioral Differences Between Mice Receiving Distinct Neuregulin Variants as Neonates; Impact on Sensitivity to MK-801. |
| Abstract | Neuregulin-1 (NRG1) is a well-recognized risk gene for schizophrenia and is often implicated in the neurodevelopmental hypothesis of this illness. Alternative splicing and proteolytic processing of the NRG1 gene produce more than 30 structural variants; however, the neuropathological roles of individual variants remain to be characterized. On the basis of the neurodevelopmental hypothesis of schizophrenia, we administered eNRG1 (0.1~1.0 ?g/g), a core epidermal growth factor-like (EGF) domain common for all splicing NRG1 variants, to neonatal mice and compared their behavioral performance with mice challenged with a full mature form of type 1 NRG1 variant. During the neonatal stage, recombinant eNRG1 protein administrated from the periphery passed the blood-brain barrier and activated its receptor (ErbB4) in the brain. In adults, the mice receiving the highest dose exhibited lower locomotor activity and deficits in prepulse inhibition and tonedependent fear learning, although the hearing reduction of the eNRG1-treated mice may explain these behavioral deficits. Neonatal eNRG1 treatment also significantly potentiated MK-801-driven locomotor activity in an eNRG1 dose-dependent manner. In parallel eNRG1 treatment enhanced MK-801-driven c-Fos induction and decreased immunoreactivity for NMDA receptor subunits in adult brain. In contrast, mice that had been treated with the same molar dose of a full mature form of type 1 NRG1 as neonates did not exhibit hypersensitivity to MK-801. However, both animal models exhibited similar hypersensitivity to methamphetamine. Collectively, our findings suggest that aberrant peripheral NRG1 signals during neurodevelopment alter later behavioral traits and auditory functions in the NRG1 subtype-dependent manner. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 74 | Med. Hypotheses 2016 Mar 88: 18-21 |
| PMID | 26880628 |
| Title | Cortical gray matter loss in schizophrenia: Could microglia be the culprit? |
| Abstract | Cortical gray matter loss in schizophrenia remains a great therapeutic difficulty. Each psychotic episode causes irreversible cortical gray matter loss, that causes the patients to never regain their previous state of functioning. Microglial cells are part of the innate immune system and their functions, among others, include phagocytosis and release of neurotrophic factors. They have a key impact on developmental and plasticity-induced removal of neuronal precursors, live-but-stressed neurons and synapses, while also stimulating synaptic growth and development. We hypothesize that microglia are the culprit for the cortical gray matter loss in schizophrenia through abnormal synaptic pruning, phagocytosis of stressed neurons and lacking neurotrophic factor release. Furthermore, we propose a research that could validate the hypotheses using serum samples of first-episode early-onset patients. By measuring the serum levels of milk fat globule-EGF factor 8 (MFG-E8), subcomponent in the classical pathway of complement activation (C1q), brain-derived neurotrophic factor (BDNF), interleukin-6 (IL-6) and interleukin-10 (IL-10), we could gain an insight into the state of microglial activation during various stages of the disease. If this hypothesis is valid, new targeted drugs could be developed in order to reduce the deterioration of cortical gray matter, thereby possibly improving negative symptoms and cognitive deficits. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 75 | Psychiatry Res 2016 Jun 240: 260-4 |
| PMID | 27138815 |
| Title | Striatal but not frontal cortical up-regulation of the epidermal growth factor receptor in rats exposed to immune activation in utero and cannabinoid treatment in adolescence. |
| Abstract | In utero maternal immune activation (MIA) and cannabinoid exposure during adolescence constitute environmental risk factors for schizophrenia. We investigated these risk factors alone and in combination ("two-hit") on epidermal growth factor receptor (EGFR) and neuregulin-1 receptor (ErbB4) levels in the rat brain. EGFR but not ErbB4 receptor protein levels were significantly increased in the nucleus accumbens and striatum of "two-hit" rats only, with no changes seen at the mRNA level. These findings support region specific EGF-system dysregulation as a plausible mechanism in this animal model of schizophrenia pathogenesis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 76 | Neurosci. Lett. 2016 Jan 612: 167-71 |
| PMID | 26687272 |
| Title | Assessment of a multi-assay biological diagnostic test for mood disorders in a Japanese population. |
| Abstract | The current diagnostic tests for mood disorders, including major depressive disorder (MDD) and bipolar disorder (BD), have limitations. Inflammatory markers, growth factors, and oxidative stress markers are involved in the pathophysiology of mood disorders. A multi-assay biological diagnostic test combining these biomarkers might improve diagnostic efficiency. The plasma levels of soluble tumor necrosis factor receptor 2 (sTNFR2), epidermal growth factor (EGF), and myeloperoxidase were measured in 40 MDD patients, 40 BD patients and 40 controls in a Japanese population. We also investigated the plasma levels of these markers in 40 patients with schizophrenia to determine the utility of these markers in differential diagnosis. The plasma levels of sTNFR2 were significantly higher in BD and schizophrenia patients than in controls. The plasma levels of EGF and myeloperoxidase were significantly higher in patients with BD than in controls. The correct classification rate obtained from discriminant analysis with sTNFR2 and EGF between controls and mood disorders was 69.2%, with a sensitivity and specificity of 62.5% and 82.5%, respectively. The correct classification rate obtained from discriminant analysis with sTNFR2 and EGF between controls and BD was 85.0%, with a sensitivity and specificity of 77.6% and 92.5%, respectively. Our results suggest that sTNFR2 and EGF could be biological markers of BD. Further studies are needed to determine the utility of these markers in diagnostic tests for mood disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |