| 1 | PLoS ONE 2009 -1 4: e5196 |
|---|---|
| PMID | 19401786 |
| Title | Transcription factor SP4 is a susceptibility gene for bipolar disorder. |
| Abstract | The SP4 transcription factor plays a critical role for both development and function of mouse hippocampus. Reduced expression of the mouse SP4 gene results in a variety of behavioral abnormalities relevant to human psychiatric disorders. The human SP4 gene is therefore examined for its association with both bipolar disorder and schizophrenia in European Caucasian and Chinese populations respectively. Out of ten SNPs selected from human SP4 genomic locus, four displayed significant association with bipolar disorder in European Caucasian families (rs12668354, p = 0.022; rs12673091, p = 0.0005; rs3735440, p = 0.019; rs11974306, p = 0.018). To replicate the genetic association, the same set of SNPs was examined in a Chinese bipolar case control sample. Four SNPs displayed significant association (rs40245, p = 0.009; rs12673091, p = 0.002; rs1018954, p = 0.001; rs3735440, p = 0.029), and two of them (rs12673091, rs3735440) were shared with positive SNPs from European Caucasian families. Considering the genetic overlap between bipolar disorder and schizophrenia, we extended our studies in Chinese trios families for schizophrenia. The SNP7 (rs12673091, p = 0.012) also displayed a significant association. The SNP7 (rs12673091) was therefore significantly associated in all three samples, and shared the same susceptibility allele (A) across all three samples. On the other hand, we found a gene dosage effect for mouse SP4 gene in the modulation of sensorimotor gating, a putative endophenotype for both schizophrenia and bipolar disorder. The deficient sensorimotor gating in SP4 hypomorphic mice was partially reversed by the administration of dopamine D2 antagonist or mood stabilizers. Both human genetic and mouse pharmacogenetic studies support SP4 gene as a susceptibility gene for bipolar disorder or schizophrenia. The studies on the role of SP4 gene in hippocampal development may provide novel insights for the contribution of hippocampal abnormalities in these psychiatric disorders. |
| SCZ Keywords | schizophrenia |
| 2 | Biochem. Soc. Trans. 2010 Apr 38: 445-51 |
| PMID | 20298200 |
| Title | Confirmed rare copy number variants implicate novel genes in schizophrenia. |
| Abstract | Understanding how cognitive processes including learning, memory, decision making and ideation are encoded by the genome is a key question in biology. Identification of sets of genes underlying human mental disorders is a path towards this objective. schizophrenia is a common disease with cognitive symptoms, high heritability and complex genetics. We have identified genes involved with schizophrenia by measuring differences in DNA copy number across the entire genome in 91 schizophrenia cases and 92 controls in the Scottish population. Our data reproduce rare and common variants observed in public domain data from >3000 schizophrenia cases, confirming known disease loci as well as identifying novel loci. We found copy number variants in PDE10A (phosphodiesterase 10A), CYFIP1 [cytoplasmic FMR1 (Fragile X mental retardation 1)-interacting protein 1], K(+) channel genes KCNE1 and KCNE2, the Down's syndrome critical region 1 gene RCAN1 (regulator of calcineurin 1), cell-recognition protein CHL1 (cell adhesion molecule with homology with L1CAM), the transcription factor SP4 (specificity protein 4) and histone deacetylase HDAC9, among others (see http://www.genes2cognition.org/SCZ-CNV). Integrating the function of these many genes into a coherent model of schizophrenia and cognition is a major unanswered challenge. |
| SCZ Keywords | schizophrenia |
| 3 | Hum. Mol. Genet. 2010 Oct 19: 3797-805 |
| PMID | 20634195 |
| Title | Reduced NMDAR1 expression in the Sp4 hypomorphic mouse may contribute to endophenotypes of human psychiatric disorders. |
| Abstract | The reduced expression of the SP4 gene in SP4 hypomorphic mice resulted in subtle vacuolization in the hippocampus as well as deficits in sensorimotor gating and contextual memory, putative endophenotypes for schizophrenia and other psychiatric disorders. In this study, we examined both spatial learning/memory and hippocampal long-term potentiation (LTP) of SP4 hypomorphic mice. Impaired spatial learning/memory and markedly reduced LTP were found. To corroborate the functional studies, the expression of N-methyl-D-aspartate (NMDA) glutamate receptors was investigated with both western blot and immunohistochemical analyses. The reduced expression of the SP4 gene decreased the level of the NR1 subunit of NMDA receptors in SP4 hypomorphic mice. In human, SP4 gene was found to be deleted sporadically in schizophrenia patients, corroborating evidence that polymorphisms of human SP4 gene are associated with schizophrenia and other psychiatric disorders. Impaired NMDA neurotransmission has been implicated in several human psychiatric disorders. As yet, it remains unclear how mutations of candidate susceptibility genes for these disorders may contribute to the disruption of NMDA neurotransmission. SP4 hypomorphic mice could therefore serve as a genetic model to investigate impaired NMDA functions resulting from loss-of-function mutations of human SP4 gene in schizophrenia and/or other psychiatric disorders. Furthermore, aberrant expression of additional genes, besides NMDAR1, likely also contributes to the behavioral abnormalities in SP4 hypomorphic mice. Thus, further investigation of the SP4 pathway may provide novel insights in our understanding of a variety of neuropsychiatric disorders. |
| SCZ Keywords | schizophrenia |
| 4 | J. Alzheimers Dis. 2012 -1 31: 537-42 |
| PMID | 22614877 |
| Title | Genetics and expression analysis of the specificity protein 4 gene (SP4) in patients with Alzheimer's disease and frontotemporal lobar degeneration. |
| Abstract | Transcription factor SP4 (Specificity protein 4) levels are increased in the brain of patients with Alzheimer's disease (AD), and SP4 colocalizes with neurofibrillary tangles. Moreover, SP4 is a susceptibility gene for bipolar disorder and schizophrenia, which share many clinical features with frontotemporal lobar degeneration (FTLD). The distribution of three tagging single nucleotide polymorphisms(SNPs)-rs9639379, rs10272006, and rs6461569-has been determined in a population of 352 patients diagnosed clinically with AD, 290 patients with FTLD, and 341 age-matched controls. Expression analysis of SP4 was performed in peripheral blood mononuclear cells (PBMC). No significant differences in either allelic or genotypic frequency of the three SNPs were found (p > 0.05), even stratifying according to gender and to the apolipoprotein E status. Significantly increased SP4 relative expression levels were observed in PBMC from patients with AD as compared with controls (7.132 ± 1.301 versus 3.396 ± 0.829, p < 0.050) and a similar trend was shown in patients with FTLD compared with controls (6.525 ± 1.500 versus 3.396 ± 0.829, p = 0.073). According to these results, SP4 gene does not act as a susceptibility factor either for AD or FTLD. However, SP4 mRNA levels are upregulated in patients, possibly resulting in an aberrant expression of downstream target genes involved in the pathogenesis of both diseases. |
| SCZ Keywords | schizophrenia |
| 5 | PLoS ONE 2013 -1 8: e66327 |
| PMID | 23823008 |
| Title | Prolonged Ketamine Effects in Sp4 Hypomorphic Mice: Mimicking Phenotypes of Schizophrenia. |
| Abstract | It has been well established that schizophrenia patients display impaired NMDA receptor (NMDAR) functions as well as exacerbation of symptoms in response to NMDAR antagonists. Abnormal NMDAR signaling presumably contributes to cognitive deficits which substantially contribute to functional disability in schizophrenia. Establishing a mouse genetic model will help investigate molecular mechanisms of hypoglutmatergic neurotransmission in schizophrenia. Here, we examined the responses of SP4 hypomorphic mice to NMDAR antagonists in electroencephalography and various behavioral paradigms. SP4 hypomorphic mice, previously reported to have reduced NMDAR1 expression and LTP deficit in hippocampal CA1, displayed increased sensitivity and prolonged responses to NMDAR antagonists. Molecular studies demonstrated reduced expression of glutamic acid decarboxylase 67 (GAD67) in both cortex and hippocampus, consistent with abnormal gamma oscillations in SP4 hypomorphic mice. On the other hand, human SP4 gene was reported to be deleted in schizophrenia. Several human genetic studies suggested the association of SP4 gene with schizophrenia and other psychiatric disorders. Therefore, elucidation of the SP4 molecular pathway in SP4 hypomorphic mice may provide novel insights to our understanding of abnormal NMDAR signaling in schizophrenia. |
| SCZ Keywords | schizophrenia |
| 6 | J Psychiatr Res 2013 Jul 47: 926-34 |
| PMID | 23540600 |
| Title | Analysis of Sp transcription factors in the postmortem brain of chronic schizophrenia: a pilot study of relationship to negative symptoms. |
| Abstract | Negative symptoms are the most resilient manifestations in schizophrenia. An imbalance in dopamine and glutamate pathways has been proposed for the emergence of these symptoms. SP1, SP3 and SP4 transcription factors regulate genes in these pathways, suggesting a possible involvement in negative symptoms. In this study, we characterized Sp factors in the brains of subjects with schizophrenia and explored a possible association with negative symptoms. We also included analysis of NR1, NR2A and DRD2 as Sp target genes. Postmortem cerebellum and prefrontal cortex from an antemortem clinically well-characterized and controlled collection of elderly subjects with chronic schizophrenia (n = 16) and control individuals (n = 14) were examined. We used the Positive and Negative Syndrome and the Clinical Global Impression schizophrenia scales, quantitative PCR and immunoblot. SP1 protein and mRNA were reduced in the prefrontal cortex in schizophrenia whereas none of Sp factors were altered in the cerebellum. However, we found that SP1, SP3 and SP4 protein levels inversely correlated with negative symptoms in the cerebellum. Furthermore, NR2A and DRD2 mRNA levels correlated with negative symptoms in the cerebellum. In the prefrontal cortex, SP1 mRNA and NR1 and DRD2 inversely correlated with these symptoms while Sp protein levels did not. This pilot study not only reinforces the involvement of SP1 in schizophrenia, but also suggests that reduced levels or function of SP1, SP4 and SP3 may participate in negative symptoms, in part through the regulation of NMDA receptor subunits and/or Dopamine D2 receptor, providing novel information about the complex negative symptoms in this disorder. |
| SCZ Keywords | schizophrenia |
| 7 | J Psychiatr Res 2013 Nov 47: 1608-14 |
| PMID | 23941741 |
| Title | Reduced expression of SP1 and SP4 transcription factors in peripheral blood mononuclear cells in first-episode psychosis. |
| Abstract | Alterations of transcription factor specificity protein 4 (SP4) and 1 (SP1) have been linked to different neuropsychiatric diseases. Reduced SP4 and SP1 protein levels in the prefrontal cortex have been associated with bipolar disorder and schizophrenia, respectively, suggesting that both factors could be involved in the pathogenesis of disorders with psychotic features. The aim of this study was to investigate whether the reduction of SP1, SP4 and SP3 protein and mRNA expression in peripheral blood mononuclear cells in the early stages of psychosis may act as a potential biomarker of these disorders. A cross-sectional study of first-episode psychosis patients (n = 14) compared to gender- and age-matched healthy controls (n = 14) was designed. Patients were recruited through the adult mental health services of Parc Sanitari Sant Joan de Déu. Protein and gene expression levels of SP1, SP4 and SP3 were assessed in peripheral blood mononuclear cells of patients with first-episode psychosis and healthy control subjects. We report that protein levels of SP1 and SP4, but not SP3, are significantly reduced in patients compared to controls. In contrast, we did not observe any differences in expression levels for SP1, SP4 or SP3 genes between patient and control groups. In patients, SP4 protein levels were significantly associated with SP1 protein levels. No association was found, however, between protein and gene expression levels for each factor. Our study shows reduced SP1 and SP4 protein levels in first-episode psychosis in lymphocytes, suggesting that these transcription factors are potential peripheral biomarkers of psychotic spectrum disorders in the early stages. |
| SCZ Keywords | schizophrenia |
| 8 | J. Neurochem. 2014 May 129: 743-52 |
| PMID | 24475768 |
| Title | Phosphorylation of the transcription factor Sp4 is reduced by NMDA receptor signaling. |
| Abstract | The regulation of transcription factor function in response to neuronal activity is important for development and function of the nervous system. The transcription factor SP4 regulates the developmental patterning of dendrites, contributes to complex processes including learning and memory, and has been linked to psychiatric disorders such as schizophrenia and bipolar disorder. Despite its many roles in the nervous system, the molecular mechanisms regulating SP4 activity are poorly understood. Here, we report a site of phosphorylation on SP4 at serine 770 that is decreased in response to membrane depolarization. Inhibition of the voltage-dependent NMDA receptor increased SP4 phosphorylation. Conversely, stimulation with NMDA reduced the levels of SP4 phosphorylation, and this was dependent on the protein phosphatase 1/2A. A phosphomimetic substitution at S770 impaired the SP4-dependent maturation of cerebellar granule neuron primary dendrites, whereas a non-phosphorylatable SP4 mutant behaved like wild type. These data reveal that transcription factor SP4 is regulated by NMDA receptor-dependent activation of a protein phosphatase 1/2A signaling pathway. Our findings also suggest that the regulated control of SP4 activity is an important mechanism governing the developmental patterning of dendrites. |
| SCZ Keywords | schizophrenia |
| 9 | J Psychiatr Res 2014 Nov 58: 189-96 |
| PMID | 25175639 |
| Title | Increased SP4 and SP1 transcription factor expression in the postmortem hippocampus of chronic schizophrenia. |
| Abstract | Altered levels of transcription factor specificity protein 4 (SP4) and 1 (SP1) in the cerebellum, prefrontal cortex and/or lymphocytes have been reported in severe psychiatric disorders, including early psychosis, bipolar disorder, and chronic schizophrenia subjects who have undergone long-term antipsychotic treatments. SP4 transgenic mice show altered hippocampal-dependent psychotic-like behaviours and altered development of hippocampal dentate gyrus. Moreover, NMDAR activity regulates SP4 function. The aim of this study was to investigate SP4 and SP1 expression levels in the hippocampus in schizophrenia, and the possible effect of antipsychotics and NMDAR blockade on SP protein levels in rodent hippocampus. We analysed SP4 and SP1 expression levels in the postmortem hippocampus of chronic schizophrenia (n = 14) and control (n = 11) subjects by immunoblot and quantitative RT-PCR. We tested the effect of NMDAR blockade on SP factors in the hippocampus of mouse treated with an acute dose of MK801. We also investigated the effect of subacute treatments with haloperidol and clozapine on SP protein levels in the rat hippocampus. We report that SP4 protein and both SP4 and SP1 mRNA expression levels are significantly increased in the hippocampus in chronic schizophrenia. Likewise, acute treatment with MK801 increased both SP4 and SP1 protein levels in mouse hippocampus. In contrast, subacute treatment with haloperidol and clozapine did not significantly alter SP protein levels in rat hippocampus. These results suggest that SP4 and SP1 upregulation may be part of the mechanisms deregulated downstream of glutamate signalling pathways in schizophrenia and might be contributing to the hippocampal-dependent cognitive deficits of the disorder. |
| SCZ Keywords | schizophrenia |
| 10 | Sci Rep 2015 -1 5: 14964 |
| PMID | 26459883 |
| Title | Characterization of spatio-temporal epidural event-related potentials for mouse models of psychiatric disorders. |
| Abstract | Distinctive features in sensory event-related potentials (ERPs) are endophenotypic biomarkers of psychiatric disorders, widely studied using electroencephalographic (EEG) methods in humans and model animals. Despite the popularity and unique significance of the mouse as a model species in basic research, existing EEG methods applicable to mice are far less powerful than those available for humans and large animals. We developed a new method for multi-channel epidural ERP characterization in behaving mice with high precision, reliability and convenience and report an application to time-domain ERP feature characterization of the SP4 hypomorphic mouse model for schizophrenia. Compared to previous methods, our spatio-temporal ERP measurement robustly improved the resolving power of key signatures characteristic of the disease model. The high performance and low cost of this technique makes it suitable for high-throughput behavioral and pharmacological studies. |
| SCZ Keywords | schizophrenia |
| 11 | Int. J. Neuropsychopharmacol. 2015 Oct 18: pyv063 |
| PMID | 26037489 |
| Title | Restoration of Sp4 in Forebrain GABAergic Neurons Rescues Hypersensitivity to Ketamine in Sp4 Hypomorphic Mice. |
| Abstract | Ketamine produces schizophrenia-like behavioral phenotypes in healthy people. Prolonged ketamine effects and exacerbation of symptoms after the administration of ketamine have been observed in patients with schizophrenia. More recently, ketamine has been used as a potent antidepressant to treat patients with major depression. The genes and neurons that regulate behavioral responses to ketamine, however, remain poorly understood. SP4 is a transcription factor for which gene expression is restricted to neuronal cells in the brain. Our previous studies demonstrated that SP4 hypomorphic mice display several behavioral phenotypes relevant to psychiatric disorders, consistent with human SP4 gene associations with schizophrenia, bipolar disorder, and major depression. Among those behavioral phenotypes, hypersensitivity to ketamine-induced hyperlocomotion has been observed in SP4 hypomorphic mice. In the present study, we used the Cre-LoxP system to restore SP4 gene expression, specifically in either forebrain excitatory or GABAergic inhibitory neurons in SP4 hypomorphic mice. Mouse behavioral phenotypes related to psychiatric disorders were examined in these distinct rescue mice. Restoration of SP4 in forebrain excitatory neurons did not rescue deficient sensorimotor gating nor ketamine-induced hyperlocomotion. Restoration of SP4 in forebrain GABAergic neurons, however, rescued ketamine-induced hyperlocomotion, but did not rescue deficient sensorimotor gating. Our studies suggest that the SP4 gene in forebrain GABAergic neurons regulates ketamine-induced hyperlocomotion. |
| SCZ Keywords | schizophrenia |
| 12 | Neuropsychopharmacology 2015 Nov 40: 2715-26 |
| PMID | 25907107 |
| Title | GlyT-1 Inhibition Attenuates Attentional But Not Learning or Motivational Deficits of the Sp4 Hypomorphic Mouse Model Relevant to Psychiatric Disorders. |
| Abstract | Serious mental illness occurs in 25% of the general population, with many disorders being neurodevelopmental, lifelong, and debilitating. The wide variation and overlap in symptoms across disorders increases the difficulty of research and treatment development. The NIMH Research Domain of Criteria initiative aims to improve our understanding of the molecular and behavioral consequences of specific neurodevelopmental mechanisms across disorders, enabling targeted treatment development. The transcription factor Specificity Protein 4 (SP4) is important for neurodevelopment and is genetically associated with both schizophrenia and bipolar disorder. Reduced SP4 expression in mice (hypomorphic) reproduces several characteristics of psychiatric disorders. We further tested the utility of SP4 hypomorphic mice as a model organism relevant to psychiatric disorders by assessing cognitive control plus effort and decision-making aspects of approach motivation using cross-species-relevant tests. SP4 hypomorphic mice exhibited impaired attention as measured by the 5-Choice Continuous Performance Test, an effect that was attenuated by glycine type-1 transporter (GlyT-1) inhibition. Hypomorphic mice also exhibited reduced motivation to work for a reward and impaired probabilistic learning. These deficits may stem from affected anticipatory reward, analogous to anhedonia in patients with schizophrenia and other psychiatric disorders. Neither positive valence deficit was attenuated by GlyT-1 treatment, suggesting that these and the attentional deficits stem from different underlying mechanisms. Given the association of SP4 gene with schizophrenia and bipolar disorder, the present studies provide support that personalized GlyT-1 inhibition may treat attentional deficits in neuropsychiatric patients with low SP4 levels. |
| SCZ Keywords | schizophrenia |
| 13 | Eur Neuropsychopharmacol 2015 Oct 25: 1650-60 |
| PMID | 26049820 |
| Title | Transcription factor SP4 phosphorylation is altered in the postmortem cerebellum of bipolar disorder and schizophrenia subjects. |
| Abstract | Transcription factors play important roles in the control of neuronal function in physiological and pathological conditions. We previously reported reduced levels of transcription factor SP4 protein, but not transcript, in the cerebellum in bipolar disorder and associated with more severe negative symptoms in schizophrenia. We have recently reported phosphorylation of SP4 at S770, which is regulated by membrane depolarization and NMDA receptor activity. The aim of this study was to investigate SP4 S770 phosphorylation in bipolar disorder and its association with negative symptoms in schizophrenia, and to explore the potential relationship between phosphorylation and protein abundance. Here we report a significant increase in SP4 phosphorylation in the cerebellum, but not the prefrontal cortex, of bipolar disorder subjects (n=10) (80% suicide) compared to matched controls (n=10). We found that SP4 phosphorylation inversely correlated with SP4 levels independently of disease status in both areas of the human brain. Moreover, SP4 phosphorylation in the cerebellum positively correlated with negative symptoms in schizophrenia subjects (n=15). Further, we observed that a phospho-mimetic mutation in truncated SP4 was sufficient to significantly decrease SP4 steady-state levels, while a non-phosphorylatable mutant showed increased stability in cultured rat cerebellar granule neurons. Our results indicate that SP4 S770 phosphorylation is increased in the cerebellum in bipolar disorder subjects that committed suicide and in severe schizophrenia subjects, and may be part of a degradation signal that controls SP4 abundance in cerebellar granule neurons. This opens the possibility that modulation of SP4 phosphorylation may contribute to the molecular pathophysiology of psychotic disorders. |
| SCZ Keywords | schizophrenia |
| 14 | PLoS ONE 2015 -1 10: e0125115 |
| PMID | 25915526 |
| Title | Phosphorylation of transcription factor specificity protein 4 is increased in peripheral blood mononuclear cells of first-episode psychosis. |
| Abstract | Altered expression of transcription factor specificity protein 4 (SP4) has been found in the postmortem brain of patients with psychiatric disorders including schizophrenia and bipolar disorder. Reduced levels of SP4 protein have recently been reported in peripheral blood mononuclear cells in first-episode psychosis. Also, SP4 levels are modulated by lithium treatment in cultured neurons. Phosphorylation of SP4 at S770 is increased in the cerebellum of bipolar disorder subjects and upon inhibition of NMDA receptor signaling in cultured neurons. The aim of this study was to investigate whether SP4 S770 phosphorylation is increased in lymphocytes of first-episode psychosis patients and the effect of lithium treatment on this phosphorylation. A cross-sectional study of S770 phosphorylation relative to total SP4 immunoreactivity using specific antibodies in peripheral blood mononuclear cells in first-episode psychosis patients (n = 14, treated with lithium or not) and matched healthy controls (n = 14) by immunoblot was designed. We also determined the effects of the prescribed drugs lithium, olanzapine or valproic acid on SP4 phosphorylation in rat primary cultured cerebellar granule neurons. We found that SP4 S770 phosphorylation was significantly increased in lymphocytes in first-episode psychosis compared to controls and decreased in patients treated with lithium compared to patients who did not receive lithium. Moreover, incubation with lithium but not olanzapine or valproic acid reduced SP4 phosphorylation in rat cultured cerebellar granule neurons. The findings presented here indicate that SP4 S770 phosphorylation is increased in lymphocytes in first-episode psychosis which may be reduced by lithium treatment in patients. Moreover, our study shows lithium treatment prevents this phosphorylation in vitro in neurons. This pilot study suggests that S770 SP4 phosphorylation could be a peripheral biomarker of psychosis, and may be regulated by lithium treatment in first-episode psychosis. |
| SCZ Keywords | schizophrenia |
| 15 | Br J Psychiatry 2016 May 208: 441-5 |
| PMID | 26450579 |
| Title | Role played by the SP4 gene in schizophrenia and major depressive disorder in the Han Chinese population. |
| Abstract | Psychiatric disorders such as schizophrenia and major depressive disorder (MDD) are likely to be caused by multiple susceptibility genes, each with small effects in increasing the risk of illness. Identifying DNA variants associated with schizophrenia and MDD is a crucial step in understanding the pathophysiology of these disorders. To investigate whether the SP4 gene plays a significant role in schizophrenia or MDD in the Han Chinese population. We focused on nine single nucleotide polymorphisms (SNPs) harbouring the SP4 gene and carried out case-control studies in 1235 patients with schizophrenia, 1045 patients with MDD and 1235 healthy controls recruited from the Han Chinese population. We found that rs40245 was significantly associated with schizophrenia in both allele and genotype distributions (Pallele = 0.0005, Pallele = 0.004 after Bonferroni correction; Pgenotype = 0.0023, Pgenotype = 0.0184 after Bonferroni correction). The rs6461563 SNP was significantly associated with schizophrenia in the allele distributions (Pallele = 0.0033, Pallele = 0.0264 after Bonferroni correction). Our results suggest that common risk factors in the SP4 gene are associated with schizophrenia, although not with MDD, in the Han Chinese population. |
| SCZ Keywords | schizophrenia |