| 1 | Biol. Psychiatry 2000 Sep 48: 381-8 |
|---|---|
| PMID | 10978721 |
| Title | Decreased muscarinic receptor binding in subjects with schizophrenia: a study of the human hippocampal formation. |
| Abstract | Acetylcholine is important to hippocampal function, including the processes of learning and memory. Patients with schizophrenia show impaired learning and memory and hippocampal dysfunction. Thus, acetylcholinergic systems may be primarily or secondarily disrupted in the hippocampal formation of schizophrenic patients. The present study tested the hypothesis that [(3)H]pirenzepine-labeled muscarinic cholinergic receptor levels are altered in the hippocampal formation of patients with schizophrenia. We have used quantitative autoradiography to measure [(3)H]pirenzepine binding to M(1) and M(4) receptors in the hippocampal formation from 15 schizophrenic and 18 nonschizophrenic subjects. The mean density of [(3)H]pirenzepine binding was reduced in all regions studied, including the dentate gyrus, subdivisions of Ammon's Horn (CA1-CA4), subiculum, and the parahippocampal gyrus, of the schizophrenic cohort. Moreover, unlike controls, there was no significant variation between the mean levels of [(3)H]pirenzepine binding across the subregions of the hippocampal formation from schizophrenic subjects. These findings provide support for a possible involvement of the muscarinic cholinergic system in the pathology and/or treatment of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 2 | Biol. Psychiatry 2000 Sep 48: 381-8 |
| PMID | 10978721 |
| Title | Decreased muscarinic receptor binding in subjects with schizophrenia: a study of the human hippocampal formation. |
| Abstract | Acetylcholine is important to hippocampal function, including the processes of learning and memory. Patients with schizophrenia show impaired learning and memory and hippocampal dysfunction. Thus, acetylcholinergic systems may be primarily or secondarily disrupted in the hippocampal formation of schizophrenic patients. The present study tested the hypothesis that [(3)H]pirenzepine-labeled muscarinic cholinergic receptor levels are altered in the hippocampal formation of patients with schizophrenia. We have used quantitative autoradiography to measure [(3)H]pirenzepine binding to M(1) and M(4) receptors in the hippocampal formation from 15 schizophrenic and 18 nonschizophrenic subjects. The mean density of [(3)H]pirenzepine binding was reduced in all regions studied, including the dentate gyrus, subdivisions of Ammon's Horn (CA1-CA4), subiculum, and the parahippocampal gyrus, of the schizophrenic cohort. Moreover, unlike controls, there was no significant variation between the mean levels of [(3)H]pirenzepine binding across the subregions of the hippocampal formation from schizophrenic subjects. These findings provide support for a possible involvement of the muscarinic cholinergic system in the pathology and/or treatment of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 3 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2000 Feb 24: 241-9 |
| PMID | 10800747 |
| Title | Morphological changes in neuropeptide Y-positive fiber in the hippocampal formation of schizophrenics. |
| Abstract | 1. The authors observed NPY-positive fibers in the CA4 area of the hippocampus from schizophrenics and normal controls using immunohistochemical techniques. 2. Positive fibers followed a straight course and were oriented to exit the CA4 region of hippocampus in normal controls. 3. Many NPY-positive fibers in the CA4 area appeared coiled or helix-like or appeared wasted and thread-like in schizophrenic brains, compared to those of normal controls. 4. These findings may indicate a dysfunction of the interneuron in the schizophrenic brain and support the hypothesis of developmental impairments of the CNS in schizophrenia, and these morphological changes in fibers may relate to schizophrenic symptoms such as memory or/and learning deterioration. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 4 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2000 Feb 24: 241-9 |
| PMID | 10800747 |
| Title | Morphological changes in neuropeptide Y-positive fiber in the hippocampal formation of schizophrenics. |
| Abstract | 1. The authors observed NPY-positive fibers in the CA4 area of the hippocampus from schizophrenics and normal controls using immunohistochemical techniques. 2. Positive fibers followed a straight course and were oriented to exit the CA4 region of hippocampus in normal controls. 3. Many NPY-positive fibers in the CA4 area appeared coiled or helix-like or appeared wasted and thread-like in schizophrenic brains, compared to those of normal controls. 4. These findings may indicate a dysfunction of the interneuron in the schizophrenic brain and support the hypothesis of developmental impairments of the CNS in schizophrenia, and these morphological changes in fibers may relate to schizophrenic symptoms such as memory or/and learning deterioration. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 5 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2000 Feb 24: 241-9 |
| PMID | 10800747 |
| Title | Morphological changes in neuropeptide Y-positive fiber in the hippocampal formation of schizophrenics. |
| Abstract | 1. The authors observed NPY-positive fibers in the CA4 area of the hippocampus from schizophrenics and normal controls using immunohistochemical techniques. 2. Positive fibers followed a straight course and were oriented to exit the CA4 region of hippocampus in normal controls. 3. Many NPY-positive fibers in the CA4 area appeared coiled or helix-like or appeared wasted and thread-like in schizophrenic brains, compared to those of normal controls. 4. These findings may indicate a dysfunction of the interneuron in the schizophrenic brain and support the hypothesis of developmental impairments of the CNS in schizophrenia, and these morphological changes in fibers may relate to schizophrenic symptoms such as memory or/and learning deterioration. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 6 | Ann. N. Y. Acad. Sci. 2000 Jun 911: 293-304 |
| PMID | 10911881 |
| Title | Amygdalo-entorhinal inputs to the hippocampal formation in relation to schizophrenia. |
| Abstract | This chapter reviews recent postmortem studies of schizophrenic brain and discusses the potential role of the amygdala in the induction of hippocampal abnormalities in this disorder. Based on available evidence, sectors CA4, CA3, and CA2, but not CA1, show preferential changes in schizophrenic subjects, although the most pronounced changes have been found in CA3 and CA2. It seems likely that the amygdala would contribute in some way to the induction of abnormalities along the trisynaptic pathway via its direct input to sectors CA3 and CA2, as well as an indirect one that involves the entorhinal cortex and its perforant path projection to the area dentata. The postmortem findings reported to date have been integrated into a working model in which decreases of inhibitory GABAergic modulation are invoked to explain the observation from a recent PET scan study (Heckers et al., 1999) that baseline metabolic activity in the hippocampus of schizophrenics is increased. In addition, however, the apparent inability of schizophrenics to increase metabolic activity in the hippocampus when challenged with a memory retrieval task may reflect a disturbance of disinhibitory modulation postulated herein to occur in sector CA3, a key relay point along the trisynaptic pathway. Overall, it seems plausible that an increase of excitatory activity entering the hippocampus from the basolateral complex via both direct and indirect pathways may make a significant contribution to the pathophysiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 7 | Ann. N. Y. Acad. Sci. 2000 Jun 911: 293-304 |
| PMID | 10911881 |
| Title | Amygdalo-entorhinal inputs to the hippocampal formation in relation to schizophrenia. |
| Abstract | This chapter reviews recent postmortem studies of schizophrenic brain and discusses the potential role of the amygdala in the induction of hippocampal abnormalities in this disorder. Based on available evidence, sectors CA4, CA3, and CA2, but not CA1, show preferential changes in schizophrenic subjects, although the most pronounced changes have been found in CA3 and CA2. It seems likely that the amygdala would contribute in some way to the induction of abnormalities along the trisynaptic pathway via its direct input to sectors CA3 and CA2, as well as an indirect one that involves the entorhinal cortex and its perforant path projection to the area dentata. The postmortem findings reported to date have been integrated into a working model in which decreases of inhibitory GABAergic modulation are invoked to explain the observation from a recent PET scan study (Heckers et al., 1999) that baseline metabolic activity in the hippocampus of schizophrenics is increased. In addition, however, the apparent inability of schizophrenics to increase metabolic activity in the hippocampus when challenged with a memory retrieval task may reflect a disturbance of disinhibitory modulation postulated herein to occur in sector CA3, a key relay point along the trisynaptic pathway. Overall, it seems plausible that an increase of excitatory activity entering the hippocampus from the basolateral complex via both direct and indirect pathways may make a significant contribution to the pathophysiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 8 | Ann. N. Y. Acad. Sci. 2000 Jun 911: 293-304 |
| PMID | 10911881 |
| Title | Amygdalo-entorhinal inputs to the hippocampal formation in relation to schizophrenia. |
| Abstract | This chapter reviews recent postmortem studies of schizophrenic brain and discusses the potential role of the amygdala in the induction of hippocampal abnormalities in this disorder. Based on available evidence, sectors CA4, CA3, and CA2, but not CA1, show preferential changes in schizophrenic subjects, although the most pronounced changes have been found in CA3 and CA2. It seems likely that the amygdala would contribute in some way to the induction of abnormalities along the trisynaptic pathway via its direct input to sectors CA3 and CA2, as well as an indirect one that involves the entorhinal cortex and its perforant path projection to the area dentata. The postmortem findings reported to date have been integrated into a working model in which decreases of inhibitory GABAergic modulation are invoked to explain the observation from a recent PET scan study (Heckers et al., 1999) that baseline metabolic activity in the hippocampus of schizophrenics is increased. In addition, however, the apparent inability of schizophrenics to increase metabolic activity in the hippocampus when challenged with a memory retrieval task may reflect a disturbance of disinhibitory modulation postulated herein to occur in sector CA3, a key relay point along the trisynaptic pathway. Overall, it seems plausible that an increase of excitatory activity entering the hippocampus from the basolateral complex via both direct and indirect pathways may make a significant contribution to the pathophysiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 9 | Schizophr. Res. 2000 Jan 41: 313-23 |
| PMID | 10708340 |
| Title | Increased dendritic MAP2 expression in the hippocampus in schizophrenia. |
| Abstract | Microtubule associated proteins (MAPs) are central to the development of normal neuronal cytoarchitecture and have been reported to be altered in schizophrenia. In 12 schizophrenic (DSM-III-R criteria) and 12 control hippocampi, we estimated the MAP2 immunoreactive dendritic length using antibodies that recognize total MAP2 (MAP2-T), and a non-phosphorylated form of MAP2 (MAP2-NP). Within the corona ammonis (CA) subregions, and the subiculum, we estimated, for each antibody, the length of the immunoreactive dendritic arborisation using a stereological length estimation technique based on Bouffon's Needle principle and image analysis computer software. Controlling for the confounding effects of age and post-mortem delay, we have found an elevation in overall MAP2-NP immunoreactive dendritic length among schizophrenic subjects in the CA3 (F=5.9, p=0.03), CA2 (F=6.5, p=0.02), CA1 (F=8.3, p=0.01) and subicular (F=9.5, p=0.008) hippocampal subregions. Similar analyses of MAP2-T immunoreactive dendritic length demonstrated significant elevations in the CA1 (F=8.3, p=0.02), CA4 (F=4.9, p=0.04) and subicular (F=7.4, p=0.01) regions. The findings of this quantitative study of increased MAP2 immunoreactive dendritic arborisation in schizophrenia are most likely to reflect either an altered dendritic arborisation or a generalised increase in levels of MAP2 with the hippocampal pyramidal neurons. These findings add to the growing literature indicating the presence of synaptodendritic abnormalities in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 10 | Schizophr. Res. 2000 Jan 41: 313-23 |
| PMID | 10708340 |
| Title | Increased dendritic MAP2 expression in the hippocampus in schizophrenia. |
| Abstract | Microtubule associated proteins (MAPs) are central to the development of normal neuronal cytoarchitecture and have been reported to be altered in schizophrenia. In 12 schizophrenic (DSM-III-R criteria) and 12 control hippocampi, we estimated the MAP2 immunoreactive dendritic length using antibodies that recognize total MAP2 (MAP2-T), and a non-phosphorylated form of MAP2 (MAP2-NP). Within the corona ammonis (CA) subregions, and the subiculum, we estimated, for each antibody, the length of the immunoreactive dendritic arborisation using a stereological length estimation technique based on Bouffon's Needle principle and image analysis computer software. Controlling for the confounding effects of age and post-mortem delay, we have found an elevation in overall MAP2-NP immunoreactive dendritic length among schizophrenic subjects in the CA3 (F=5.9, p=0.03), CA2 (F=6.5, p=0.02), CA1 (F=8.3, p=0.01) and subicular (F=9.5, p=0.008) hippocampal subregions. Similar analyses of MAP2-T immunoreactive dendritic length demonstrated significant elevations in the CA1 (F=8.3, p=0.02), CA4 (F=4.9, p=0.04) and subicular (F=7.4, p=0.01) regions. The findings of this quantitative study of increased MAP2 immunoreactive dendritic arborisation in schizophrenia are most likely to reflect either an altered dendritic arborisation or a generalised increase in levels of MAP2 with the hippocampal pyramidal neurons. These findings add to the growing literature indicating the presence of synaptodendritic abnormalities in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 11 | Mol. Psychiatry 2000 Nov 5: 654-63, 571 |
| PMID | 11126396 |
| Title | Reduction in Reelin immunoreactivity in hippocampus of subjects with schizophrenia, bipolar disorder and major depression. |
| Abstract | Accumulation of neurobiological knowledge points to neurodevelopmental origins for certain psychotic and mood disorders. Recent landmark postmortem reports implicate Reelin, a secretory glycoprotein responsible for normal lamination of brain, in the pathology of schizophrenia and bipolar disorders. We employed quantitative immunocytochemistry to measure levels of Reelin protein in various compartments of hippocampal formation in subjects diagnosed with schizophrenia, bipolar disorder and major depression compared to normal controls. Significant reductions were observed in Reelin-positive adjusted cell densities in the dentate molecular layer (ANOVA, P < 0.001), CA4 area (ANOVA, P < 0.001), total hippocampal area (ANOVA, P < 0.038) and in Reelin-positive cell counts in CA4 (ANOVA, P < 0.042) of schizophrenics vs controls. Adjusted Reelin-positive cell densities were also reduced in CA4 areas of subjects with bipolar disorder (ANOVA, P < 0.001) and nonsignificantly in those with major depression. CA4 areas were also significantly reduced in schizophrenic (ANOVA, P < 0.009) patients. No significant effects of confounding variables were found. The exception was that family history of psychiatric illness correlated strongly with Reelin reductions in several areas of hippocampus (CA4, adjusted cell density, F = 13.77, P = 0.001). We present new immunocytochemical evidence showing reductions in Reelin expression in hippocampus of subjects with schizophrenia, bipolar disorder and major depression and confirm recent reports documenting a similar deficit involving Reelin expression in brains of subjects with schizophrenia and bipolar disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 12 | Mol. Psychiatry 2000 Nov 5: 654-63, 571 |
| PMID | 11126396 |
| Title | Reduction in Reelin immunoreactivity in hippocampus of subjects with schizophrenia, bipolar disorder and major depression. |
| Abstract | Accumulation of neurobiological knowledge points to neurodevelopmental origins for certain psychotic and mood disorders. Recent landmark postmortem reports implicate Reelin, a secretory glycoprotein responsible for normal lamination of brain, in the pathology of schizophrenia and bipolar disorders. We employed quantitative immunocytochemistry to measure levels of Reelin protein in various compartments of hippocampal formation in subjects diagnosed with schizophrenia, bipolar disorder and major depression compared to normal controls. Significant reductions were observed in Reelin-positive adjusted cell densities in the dentate molecular layer (ANOVA, P < 0.001), CA4 area (ANOVA, P < 0.001), total hippocampal area (ANOVA, P < 0.038) and in Reelin-positive cell counts in CA4 (ANOVA, P < 0.042) of schizophrenics vs controls. Adjusted Reelin-positive cell densities were also reduced in CA4 areas of subjects with bipolar disorder (ANOVA, P < 0.001) and nonsignificantly in those with major depression. CA4 areas were also significantly reduced in schizophrenic (ANOVA, P < 0.009) patients. No significant effects of confounding variables were found. The exception was that family history of psychiatric illness correlated strongly with Reelin reductions in several areas of hippocampus (CA4, adjusted cell density, F = 13.77, P = 0.001). We present new immunocytochemical evidence showing reductions in Reelin expression in hippocampus of subjects with schizophrenia, bipolar disorder and major depression and confirm recent reports documenting a similar deficit involving Reelin expression in brains of subjects with schizophrenia and bipolar disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 13 | Mol. Psychiatry 2000 Nov 5: 654-63, 571 |
| PMID | 11126396 |
| Title | Reduction in Reelin immunoreactivity in hippocampus of subjects with schizophrenia, bipolar disorder and major depression. |
| Abstract | Accumulation of neurobiological knowledge points to neurodevelopmental origins for certain psychotic and mood disorders. Recent landmark postmortem reports implicate Reelin, a secretory glycoprotein responsible for normal lamination of brain, in the pathology of schizophrenia and bipolar disorders. We employed quantitative immunocytochemistry to measure levels of Reelin protein in various compartments of hippocampal formation in subjects diagnosed with schizophrenia, bipolar disorder and major depression compared to normal controls. Significant reductions were observed in Reelin-positive adjusted cell densities in the dentate molecular layer (ANOVA, P < 0.001), CA4 area (ANOVA, P < 0.001), total hippocampal area (ANOVA, P < 0.038) and in Reelin-positive cell counts in CA4 (ANOVA, P < 0.042) of schizophrenics vs controls. Adjusted Reelin-positive cell densities were also reduced in CA4 areas of subjects with bipolar disorder (ANOVA, P < 0.001) and nonsignificantly in those with major depression. CA4 areas were also significantly reduced in schizophrenic (ANOVA, P < 0.009) patients. No significant effects of confounding variables were found. The exception was that family history of psychiatric illness correlated strongly with Reelin reductions in several areas of hippocampus (CA4, adjusted cell density, F = 13.77, P = 0.001). We present new immunocytochemical evidence showing reductions in Reelin expression in hippocampus of subjects with schizophrenia, bipolar disorder and major depression and confirm recent reports documenting a similar deficit involving Reelin expression in brains of subjects with schizophrenia and bipolar disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 14 | Mol. Psychiatry 2000 Jul 5: 425-32 |
| PMID | 10889554 |
| Title | Hippocampal synaptic pathology in schizophrenia, bipolar disorder and major depression: a study of complexin mRNAs. |
| Abstract | Complexin (cx) I and cx II are synaptic proteins preferentially expressed by inhibitory and excitatory hippocampal neurons respectively. We previously reported decreased hippocampal formation cx mRNA and protein expression in schizophrenia, with a greater loss of cx II than cx I. The present in situ hybridization study was both an attempt at replication, and an extension to include bipolar and unipolar mood disorders, using sections from the Stanley Foundation brain series. In schizophrenia, both mRNAs were decreased in some hippocampal subfields, especially CA4, but were preserved in subiculum. The cx II/cx I mRNA ratio was unchanged. In bipolar disorder, the mRNAs were reduced in CA4, subiculum and parahippocampal gyrus, with the deficit in subiculum being diagnostically specific. No alterations in cx mRNAs were found in major depression. Treatment of rats with antipsychotics (haloperidol or chlorpromazine) for 2 weeks had no effect on hippocampal cx mRNAs. These data replicate the finding of decreased cx I and cx II expression in the hippocampus in schizophrenia and show a similar or greater abnormality in bipolar disorder. Non-replication of the cx II > cx I mRNA loss in schizophrenia means that the hypothesis of a preferential involvement of excitatory connections was not supported. The results extend the emerging evidence that altered circuitry may be a component of the neuroanatomy of both schizophrenia and bipolar mood disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 15 | Hippocampus 2001 -1 11: 508-19 |
| PMID | 11732704 |
| Title | Neuropathological studies of synaptic connectivity in the hippocampal formation in schizophrenia. |
| Abstract | Cytoarchitectural changes in the hippocampal formation have been prominent among the various neuropathological abnormalities reported in schizophrenia. Replicated positive findings include decreased neuronal size and alterations in presynaptic and dendritic markers. These findings, in the absence of neurodegenerative changes, suggest that there are alterations in the neural circuitry in schizophrenia. These may represent the anatomical correlate of the aberrant functional connectivity described in neuroimaging studies, which in turn contributes to the psychotic and cognitive symptomatology of the disorder. The identity of the affected hippocampal circuits remains unclear; there is evidence for both glutamatergic and GABAergic involvement, and perhaps for a gradient of pathology in which changes are most apparent in CA4 and the subiculum, and least in CA1. The data, their interpretation, and their limitations are discussed, with particular emphasis upon molecular and immunological studies of synaptic protein gene expression. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 16 | Hippocampus 2001 -1 11: 492-507 |
| PMID | 11732703 |
| Title | Effects of pre- and postnatal corticosterone exposure on the rat hippocampal GABA system. |
| Abstract | Several lines of evidence have implicated prenatal stress and the hippocampal GABA system in the pathophysiology of schizophrenia, and prenatal stress is believed to increase the risk for schizophrenia through alterations of this neurotransmitter. To explore this hypothesis, we treated male rats pre- and/or postnatally (P48 and P60) with either corticosterone (CORT) or vehicle to establish three study groups: VVV, receiving vehicle at all three time points; VCC, receiving vehicle prenatally and CORT at both postnatal timepoints; and CCC, receiving CORT at all three timepoints. Animals were sacrificed at either 24 h or 5 days after final injection and examined for mRNA levels of GAD65, GAD67, and the GABA(A) receptor subunits alpha2 and gamma2. At 24 h, GAD65 mRNA was decreased in CA1, CA2, CA4, and dentate gyrus (DG) of VCC rats; this effect was either decreased or reversed in CCC-treated animals. No effect was detected in GAD67 mRNA at 24 h. At 5 days, CORT treatment increased GAD67 mRNA levels in CA1, CA3, and DG. Prenatal treatment with CORT was associated with increased responsiveness only in CA3 and DG. For the GABAA receptor, alpha2 subunit mRNA did not show any change in response to CORT treatment, while that for the gamma2 subunit was decreased in CA2 of both VCC- and CCC-treated animals. Consistent with gamma2 subunit mRNA decreases, benzodiazepine (BZ) receptor binding activity was decreased in CA2 with CORT treatment. Prenatal CORT exposure neither increased nor decreased this effect. These results demonstrate that CORT administration is associated with a complex regulation of mRNA expression for pre- and postnatal aspects of the hippocampal GABA system. Under these conditions, prenatal exposure to CORT may sensitize some of these effects, but does not fundamentally alter the nature of this response. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 17 | J. Comp. Neurol. 2001 Mar 431: 129-38 |
| PMID | 11169995 |
| Title | Amygdalar activation alters the hippocampal GABA system: "partial" modelling for postmortem changes in schizophrenia. |
| Abstract | Abnormalities in amygdala and hippocampus have been shown to coexist in schizophrenia (SZ). In the hippocampus, compelling evidence suggests that a disruption of GABA neurotransmission is present mainly in sectors CA4, CA3, and CA2. The amygdala sends important inputs to the hippocampus and is also believed to have a defective GABA system in schizophrenia. To explore the possibility that changes in the hippocampal GABAergic system could be related to an increased inflow of activity originating in the amygdala, a "partial" animal model has been developed. In awake, freely moving, rats a GABA(A) receptor antagonist was infused locally into the basolateral nuclear complex of the amygdala (BLn). Within 2 hours, a decreased density of both the 65- and 67-kDa isoforms of glutamate decarboxylase (GAD(65) and GAD(67)) -immunoreactive (IR) terminals was detected on neuron somata in sectors CA3 and CA2, but not in CA1, CA3, or dentate gyrus. An increase of GAD(67)-IR somata was also found in the dentate gyrus and CA4. In anterograde tracer studies, amygdalo-hippocampal projection fibers were exclusively found in CA3 and CA2, but not CA1. Taken together, these results indicate that activation of amygdalo-hippocampal afferents is associated with the induction of significant changes in the GABA system of the hippocampus, with a subregional distribution that is remarkably similar to that found in SZ. Under pathologic conditions, an excessive discharge of excitatory activity emanating from the amygdala could be capable of altering inhibitory modulation along the trisynaptic pathway. This mechanism may potentially contribute to disturbances of GABAergic function in the major psychoses. Such "partial" rodent modelling provides an important strategy for deciphering the effect of altered cortico-limbic circuits in SZ. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 18 | Schizophr. Res. 2002 Nov 58: 43-53 |
| PMID | 12363389 |
| Title | Reduction of chromogranin B-like immunoreactivity in distinct subregions of the hippocampus from individuals with schizophrenia. |
| Abstract | Synaptic disturbances may play a key role in the pathophysiology of schizophrenia. This study was designed to further investigate possible synaptic alterations in the brains of chronic schizophrenic patients. Chromogranin B was applied as a marker for large dense core vesicles and synapsin I as a protein associated with the synaptic vesicle membrane. The distribution and density of chromogranin B-and synapsin I-like immunoreactivity in subregions of the hippocampus was compared between controls (n = 16) and patients with schizophrenia (n = 17). The overall distribution of hippocampal chromogranin B- and synapsin I-like immunoreactivity was similar in controls and in schizophrenic patients with the highest densities in the terminal field of mossy fibers and in the inner molecular layer of the dentate gyrus. In schizophrenic hippocampi, a significant reduction in the density of chromogranin B-like immunoreactivity was found in the CA4 and CA3 but not in the CA1 area of the dentate gyrus based on computerized image analysis. The loss of immunoreactivity was localized to mossy fibers and terminals surrounding hilar interneurons. Double-labelling immunohistochemistry revealed that synapsin I was co-expressed with chromogranin B in these neuronal structures and was also significantly reduced in schizophrenic hippocampi. The present study demonstrates an area-specific reduction of chromogranin B which is paralleled by a decrease of synapsin I. The loss of presynaptic proteins involved in distinct steps of exocytosis may cause complex synaptic disturbances in specific hippocampal subregions resulting in an imbalanced neurotransmitter availability in schizophrenic patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 19 | Schizophr. Res. 2002 Nov 58: 43-53 |
| PMID | 12363389 |
| Title | Reduction of chromogranin B-like immunoreactivity in distinct subregions of the hippocampus from individuals with schizophrenia. |
| Abstract | Synaptic disturbances may play a key role in the pathophysiology of schizophrenia. This study was designed to further investigate possible synaptic alterations in the brains of chronic schizophrenic patients. Chromogranin B was applied as a marker for large dense core vesicles and synapsin I as a protein associated with the synaptic vesicle membrane. The distribution and density of chromogranin B-and synapsin I-like immunoreactivity in subregions of the hippocampus was compared between controls (n = 16) and patients with schizophrenia (n = 17). The overall distribution of hippocampal chromogranin B- and synapsin I-like immunoreactivity was similar in controls and in schizophrenic patients with the highest densities in the terminal field of mossy fibers and in the inner molecular layer of the dentate gyrus. In schizophrenic hippocampi, a significant reduction in the density of chromogranin B-like immunoreactivity was found in the CA4 and CA3 but not in the CA1 area of the dentate gyrus based on computerized image analysis. The loss of immunoreactivity was localized to mossy fibers and terminals surrounding hilar interneurons. Double-labelling immunohistochemistry revealed that synapsin I was co-expressed with chromogranin B in these neuronal structures and was also significantly reduced in schizophrenic hippocampi. The present study demonstrates an area-specific reduction of chromogranin B which is paralleled by a decrease of synapsin I. The loss of presynaptic proteins involved in distinct steps of exocytosis may cause complex synaptic disturbances in specific hippocampal subregions resulting in an imbalanced neurotransmitter availability in schizophrenic patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 20 | Am J Psychiatry 2002 May 159: 821-8 |
| PMID | 11986137 |
| Title | Estimated neuronal populations and volumes of the hippocampus and its subfields in schizophrenia. |
| Abstract | It has been suggested that the primary focus of the pathological process in schizophrenia is on the limbic system, and there have been several postmortem reports of changes in the histological structure or volume of the hippocampus, as well as a larger number of MRI reports of volume reductions. There are conflicting findings, however, with both techniques. The authors conducted a study of the gross and subfield structure and cellular composition of the hippocampus in postmortem brains from 30 patients with DSM-IV-diagnosed schizophrenia (13 women, 17 men) and 29 comparison subjects with no psychopathology (14 women, 15 men). Stereological sampling procedures were applied to 25-microm-thick coronal paraffin sections taken at 5-mm intervals throughout the formalin-fixed hippocampus. Subfields were defined as the dentate fascia, the hilus (CA4), an amalgamation of the CA2 and CA3 subfields, the CA1 subfield, and the subiculum. Volumes, cell densities, and cell numbers of the subfields were assessed microscopically, and the volume of the hippocampus was estimated from both photographs and histological slides of the coronal slices. As assessed from histologically stained slides, the volumes of the hippocampus and its subfields did not differ between patients and comparison subjects. Left-sided reduction in hippocampal volumes estimated from photographs, which may have included parahippocampal tissue, was not confirmed on histological examination. No significant differences were observed between patients and comparison subjects in the cellular composition of the hippocampus. These findings do not support a primary alteration of the hippocampus in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 21 | Arch. Gen. Psychiatry 2002 Jun 59: 521-9 |
| PMID | 12044194 |
| Title | Differential hippocampal expression of glutamic acid decarboxylase 65 and 67 messenger RNA in bipolar disorder and schizophrenia. |
| Abstract | Expression of messenger RNA (mRNA) for the gamma-aminobutyric acid (GABA)-synthesizing enzyme, glutamic acid decarboxylase (GAD), in the prefrontal cortex and the number of GABAergic neurons in the hippocampus are reduced in schizophrenia and bipolar disorder. We tested the hypothesis that the expression of the 2 isoforms, one 65 kd (GAD(65)) and the other 67 kd (GAD(67)), is differentially affected in the hippocampus in schizophrenia and bipolar disorder. Hippocampal sections from 15 subjects in 3 groups (control subjects and subjects with schizophrenia and bipolar disorder) were studied using an in situ hybridization protocol with sulfur 35-labeled complementary riboprobes for GAD(65) and GAD(67) mRNA. Emulsion-dipped slides were analyzed for the density of GAD mRNA-positive neurons in 4 sectors of the hippocampus and for the cellular expression level of both GAD mRNAs. The density of GAD(65) and GAD(67) mRNA-positive neurons was decreased by 45% and 43%, respectively, in subjects with bipolar disorder, but only 14% and 4%, respectively, in subjects with schizophrenia. The decreased density of GAD(65) mRNA-positive neurons in subjects with bipolar disorder was significant in sectors CA2/3 and dentate gyrus, and that of GAD(67) mRNA-positive neurons was significant in CA4, but not other hippocampal sectors. Cellular GAD(65) mRNA expression was significantly decreased in subjects with bipolar disorder, particularly in CA4, but not in schizophrenic subjects. Cellular GAD(67) mRNA expression was normal in both groups. We have found a region-specific deficit of GAD(65) and GAD(67) mRNA expression in bipolar disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 22 | Arch. Gen. Psychiatry 2002 Jun 59: 521-9 |
| PMID | 12044194 |
| Title | Differential hippocampal expression of glutamic acid decarboxylase 65 and 67 messenger RNA in bipolar disorder and schizophrenia. |
| Abstract | Expression of messenger RNA (mRNA) for the gamma-aminobutyric acid (GABA)-synthesizing enzyme, glutamic acid decarboxylase (GAD), in the prefrontal cortex and the number of GABAergic neurons in the hippocampus are reduced in schizophrenia and bipolar disorder. We tested the hypothesis that the expression of the 2 isoforms, one 65 kd (GAD(65)) and the other 67 kd (GAD(67)), is differentially affected in the hippocampus in schizophrenia and bipolar disorder. Hippocampal sections from 15 subjects in 3 groups (control subjects and subjects with schizophrenia and bipolar disorder) were studied using an in situ hybridization protocol with sulfur 35-labeled complementary riboprobes for GAD(65) and GAD(67) mRNA. Emulsion-dipped slides were analyzed for the density of GAD mRNA-positive neurons in 4 sectors of the hippocampus and for the cellular expression level of both GAD mRNAs. The density of GAD(65) and GAD(67) mRNA-positive neurons was decreased by 45% and 43%, respectively, in subjects with bipolar disorder, but only 14% and 4%, respectively, in subjects with schizophrenia. The decreased density of GAD(65) mRNA-positive neurons in subjects with bipolar disorder was significant in sectors CA2/3 and dentate gyrus, and that of GAD(67) mRNA-positive neurons was significant in CA4, but not other hippocampal sectors. Cellular GAD(65) mRNA expression was significantly decreased in subjects with bipolar disorder, particularly in CA4, but not in schizophrenic subjects. Cellular GAD(67) mRNA expression was normal in both groups. We have found a region-specific deficit of GAD(65) and GAD(67) mRNA expression in bipolar disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 23 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2003 Aug 27: 801-7 |
| PMID | 12921913 |
| Title | Immunohistochemical study of brain-derived neurotrophic factor and its receptor, TrkB, in the hippocampal formation of schizophrenic brains. |
| Abstract | Recently, the pathogenesis of schizophrenia has been investigated from the perspective of neurodevelopmental dysfunction theory. On the other hand, it has been indicated that neurotrophic factors, such as nerve growth factors, brain-derived neurotrophic factor (BDNF), and neurotrophin-3, are significantly involved in the development and functional differences of central nervous system (CNS). Some reports proposed that the dysfunction of these factors could explain the pathogenesis of schizophrenia possibly. In this study, the authors investigated immunohistochemically the distribution and/or morphology of BDNF and TrkB, its peculiar receptor, in the hippocampal formation of schizophrenic brain. As a result, BDNF-positive pyramidal cells in the CA2 and neurons in the CA3 and the field of the CA4 were intensely stained compared to those of normal control. Staining of TrkB-positive neurons showed a signet-ring like shape in the hippocampus of normal control brains. Such figures were not observed on staining of those neurons from schizophrenic brains. In the control cases, TrkB-immunopositive varicose fibers were frequently seen. Those observed differences between schizophrenic and normal cases may indicate the existence of dysfunction of BDNF and TrkB in schizophrenic brain, and this dysfunction may be one of the factors involved in the pathogenesis of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 24 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2003 Aug 27: 801-7 |
| PMID | 12921913 |
| Title | Immunohistochemical study of brain-derived neurotrophic factor and its receptor, TrkB, in the hippocampal formation of schizophrenic brains. |
| Abstract | Recently, the pathogenesis of schizophrenia has been investigated from the perspective of neurodevelopmental dysfunction theory. On the other hand, it has been indicated that neurotrophic factors, such as nerve growth factors, brain-derived neurotrophic factor (BDNF), and neurotrophin-3, are significantly involved in the development and functional differences of central nervous system (CNS). Some reports proposed that the dysfunction of these factors could explain the pathogenesis of schizophrenia possibly. In this study, the authors investigated immunohistochemically the distribution and/or morphology of BDNF and TrkB, its peculiar receptor, in the hippocampal formation of schizophrenic brain. As a result, BDNF-positive pyramidal cells in the CA2 and neurons in the CA3 and the field of the CA4 were intensely stained compared to those of normal control. Staining of TrkB-positive neurons showed a signet-ring like shape in the hippocampus of normal control brains. Such figures were not observed on staining of those neurons from schizophrenic brains. In the control cases, TrkB-immunopositive varicose fibers were frequently seen. Those observed differences between schizophrenic and normal cases may indicate the existence of dysfunction of BDNF and TrkB in schizophrenic brain, and this dysfunction may be one of the factors involved in the pathogenesis of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 25 | Eur. J. Neurosci. 2003 Sep 18: 1197-205 |
| PMID | 12956718 |
| Title | Expression of NMDA receptor NR1, NR2A and NR2B subunit mRNAs during development of the human hippocampal formation. |
| Abstract | The N-methyl-d-aspartate receptor plays a critical role in the formation and maintenance of synapses during brain development. In the rodent, changes in subunit expression and assembly of the heteromeric receptor complex accompany these maturational processes. However, little is known about N-methyl-d-aspartate receptor subunit expression during human brain development. We used in situ hybridization to examine the distribution and relative abundance of NR1, NR2A and NR2B subunit messenger ribonucleic acids in the hippocampal formation and adjacent cortex of 34 human subjects at five stages of life (neonate, infant, adolescent, young adult and adult). At all ages, the three messenger ribonucleic acids were expressed in all subfields, predominantly by pyramidal neurons, granule cells and polymorphic hilar cells. However, their abundance varied across ontogeny. Levels of NR1 messenger ribonucleic acid in CA4, CA3 and CA2 subfields were significantly lower in the neonate than all other age groups. In the dentate gyrus, subiculum and parahippocampal gyrus, NR2B messenger ribonucleic acid levels were higher in the neonate than in older age groups. NR2A messenger ribonucleic acid levels remained constant, leading to an age-related increase in NR2A/2B transcript ratio. We conclude that N-methyl-d-aspartate receptor subunit messenger ribonucleic acids are differentially expressed during postnatal development of the human hippocampus, with a pattern similar but not identical to that seen in the rodent. Changes in subunit composition may thus contribute to maturational differences in human hippocampal N-methyl-d-aspartate receptor function, and to their role in the pathophysiology of schizophrenia and other neurodevelopmental disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 26 | Hippocampus 2004 -1 14: 876-94 |
| PMID | 15382257 |
| Title | Long-term effects of amygdala GABA receptor blockade on specific subpopulations of hippocampal interneurons. |
| Abstract | Growing evidence indicates that the amygdala modulates hippocampal functions. To test the hypothesis that this modulation may involve long-lasting effects on interneuronal networks in the hippocampus, changes in the expression of neurochemical markers specific for different interneuronal subpopulations were assessed in adult rats 96 h following acute infusion of low doses of the GABAA receptor antagonist picrotoxin into the amygdala. The numerical density (Nd) of somata showing immunoreactivity (IR) for parvalbumin (PVB) was decreased in dentate gyrus (DG) and the CA4-2 region, while that of calretinin (CR)-IR was decreased in DG and CA2. The Nd of calbindin D28k (CB)-IR somata was decreased in CA3-2. The densities of axon terminals arising from PVB-IR and cholecystokinin (CCK)-IR basket neurons were also altered, with those of CCK-IR terminals increased across all sectors, while PVB-IR terminals were decreased only in the CA region. Increases in CCK-IR terminals were paralleled by increases of terminals with IR for the 65-kD isoform of glutamate decarboxylase (GAD65). Mixed-effects statistical models, adapted specifically for these analyses, indicated that perturbations of amygdalar inputs to the hippocampus significantly alter the drive that hippocampal PVB-, CR-, and CB-IR neurons within the dentate gyrus/CA4 region exercise on CCK-IR terminals within the same region as well as in CA3-1. These results suggest that amygdalar modulation of specific neuronal subpopulations may induce lasting and far-reaching changes in the hippocampus during normal functioning, as well as in diseases involving a disruption of amygdalar activity. In particular, changes in specific interneuronal markers within selective hippocampal sectors detected in the present results are strikingly similar to those reported in this region in schizophrenia. These similarities suggest that, in this disease, a disruption of GABAergic transmission within the amygdala may play a significant role in the induction of abnormalities in the hippocampus. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 27 | Am J Psychiatry 2004 Oct 161: 1848-55 |
| PMID | 15465982 |
| Title | Reduced spinophilin but not microtubule-associated protein 2 expression in the hippocampal formation in schizophrenia and mood disorders: molecular evidence for a pathology of dendritic spines. |
| Abstract | Aberrant synaptic connectivity may underlie the involvement of the hippocampus in schizophrenia. There is reasonable neuropathological evidence for a presynaptic pathology but few studies of the postsynaptic component. This study tested the hypothesis that hippocampal dendritic pathology is also present in schizophrenia. Using in situ hybridization in sections of hippocampal formation from 10 patients with schizophrenia, 10 patients with mood disorders (three with bipolar disorder and seven with major depression), and 10 healthy comparison subjects, the authors examined the expression of two important dendritic genes: spinophilin, which serves as a marker of dendritic spines, and microtubule-associated protein 2 (MAP2), an overall dendritic marker. The patients with schizophrenia had lower levels of spinophilin mRNA in CA4 (hilus), CA3, the subiculum, and the entorhinal cortex than did the normal comparison subjects. The mood disorder group showed similar differences from the comparison group. MAP2 and cyclophilin mRNA did not differ between the groups in any subfield. Decreased spinophilin but unchanged MAP2 expression provides molecular evidence for a hippocampal dendritic pathology in schizophrenia that preferentially affects the spines. As spines are the target of most glutamatergic synapses, the data extend the evidence that excitatory synapses are particularly affected. Similar dendritic spine pathology may also occur in mood disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 28 | Brain Res. Bull. 2006 Jul 70: 221-7 |
| PMID | 16861106 |
| Title | Hippocampal FGF-2 and FGFR1 mRNA expression in major depression, schizophrenia and bipolar disorder. |
| Abstract | FGF-2 is important for stem cell proliferation, neocortical development and adult neuronal survival and growth. Reduced frontal cortical FGF-2 expression is described in major depression and is attenuated by antidepressants. We determined the distribution of hippocampal FGF-2 and its receptor (FGFR1) mRNA in post-mortem brains of people who suffered from major depression, bipolar disorder and schizophrenia and those of controls. FGF-2 and FGFR1 mRNA were measured within hippocampal CA1, CA4 regions and the dentate gyrus (DG), using in situ hybridization. Within hippocampal regions, cellular staining was compared between diagnostic groups, using repeated measures analysis of variance. The density of FGF-2 mRNA+ cells in CA4 was reduced in depression compared to controls. The percentage of FGFR1 mRNA+ cells was higher in depression (CA1 and CA4) and schizophrenia (CA4) than in controls. FGFR1 mRNA expression was higher in depression than in the other groups in CA1, CA4 and DG. Overall FGF-2 mRNA expression was higher in DG than in CA1 and CA4. We found raised measures of FGFR1 mRNA+ in major depression and, less so, in schizophrenia, along with reduced FGF-2 mRNA density in depression. Perturbations of FGF regulation could be relevant to the pathogenesis of both disorders as FGF-2 and FGFR1 are implicated in normal hippocampal synaptology, stem cell recruitment, and connectivity, and are modulated by corticosteroids. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 29 | Braz. J. Med. Biol. Res. 2008 Apr 41: 333-41 |
| PMID | 18392456 |
| Title | Expression of neuronal nitric oxide synthase in the hippocampal formation in affective disorders. |
| Abstract | Hippocampal output is increased in affective disorders and is mediated by increased glutamatergic input via N-methyl-D-aspartate (NMDA) receptor and moderated by antidepressant treatment. Activation of NMDA receptors by glutamate evokes the release of nitric oxide (NO) by the activation of neuronal nitric oxide synthase (nNOS). The human hippocampus contains a high density of NMDA receptors and nNOS-expressing neurons suggesting the existence of an NMDA-NO transduction pathway which can be involved in the pathogenesis of affective disorders. We tested the hypothesis that nNOS expression is increased in the human hippocampus from affectively ill patients. Immunocytochemistry was used to demonstrate nNOS-expressing neurons in sections obtained from the Stanley Consortium postmortem brain collection from patients with major depression (MD, N = 15), bipolar disorder (BD, N = 15), and schizophrenia (N = 15) and from controls (N = 15). nNOS-immunoreactive (nNOS-IR) and Nissl-stained neurons were counted in entorhinal cortex, hippocampal CA1, CA2, CA3, and CA4 subfields, and subiculum. The numbers of Nissl-stained neurons were very similar in different diagnostic groups and correlated significantly with the number of nNOS-IR neurons. Both the MD and the BD groups had greater number of nNOS-IR neurons/400 microm(2) in CA1 (mean +/- SEM: MD = 9.2 +/- 0.6 and BD = 8.4 +/- 0.6) and subiculum (BD = 6.7 +/- 0.4) when compared to control group (6.6 +/- 0.5) and this was significantly more marked in samples from the right hemisphere. These changes were specific to affective disorders since no changes were seen in the schizophrenic group (6.7 +/- 0.8). The results support the current view of the NMDA-NO pathway as a target for the pathophysiology of affective disorders and antidepressant drug development. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 30 | Braz. J. Med. Biol. Res. 2008 Apr 41: 333-41 |
| PMID | 18392456 |
| Title | Expression of neuronal nitric oxide synthase in the hippocampal formation in affective disorders. |
| Abstract | Hippocampal output is increased in affective disorders and is mediated by increased glutamatergic input via N-methyl-D-aspartate (NMDA) receptor and moderated by antidepressant treatment. Activation of NMDA receptors by glutamate evokes the release of nitric oxide (NO) by the activation of neuronal nitric oxide synthase (nNOS). The human hippocampus contains a high density of NMDA receptors and nNOS-expressing neurons suggesting the existence of an NMDA-NO transduction pathway which can be involved in the pathogenesis of affective disorders. We tested the hypothesis that nNOS expression is increased in the human hippocampus from affectively ill patients. Immunocytochemistry was used to demonstrate nNOS-expressing neurons in sections obtained from the Stanley Consortium postmortem brain collection from patients with major depression (MD, N = 15), bipolar disorder (BD, N = 15), and schizophrenia (N = 15) and from controls (N = 15). nNOS-immunoreactive (nNOS-IR) and Nissl-stained neurons were counted in entorhinal cortex, hippocampal CA1, CA2, CA3, and CA4 subfields, and subiculum. The numbers of Nissl-stained neurons were very similar in different diagnostic groups and correlated significantly with the number of nNOS-IR neurons. Both the MD and the BD groups had greater number of nNOS-IR neurons/400 microm(2) in CA1 (mean +/- SEM: MD = 9.2 +/- 0.6 and BD = 8.4 +/- 0.6) and subiculum (BD = 6.7 +/- 0.4) when compared to control group (6.6 +/- 0.5) and this was significantly more marked in samples from the right hemisphere. These changes were specific to affective disorders since no changes were seen in the schizophrenic group (6.7 +/- 0.8). The results support the current view of the NMDA-NO pathway as a target for the pathophysiology of affective disorders and antidepressant drug development. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 31 | Hippocampus 2008 -1 18: 169-81 |
| PMID | 17960646 |
| Title | The amygdala modulates neuronal activation in the hippocampus in response to spatial novelty. |
| Abstract | Emerging evidence indicates that the amygdala and the hippocampus play an important role in the pathophysiology of major psychotic disorders. Consistent with this evidence, and with data indicating amygdala modulation of hippocampal activity, animal model investigations have shown that a disruption of amygdala activity induces neurochemical changes in the hippocampus that are similar to those detected in subjects with schizophrenia. With the present study, we used induction of the immediate early gene Fos, to test the hypothesis that the amygdala may affect neuronal activation of the hippocampus in response to different spatial environments (familiar, modified, and novel). Exploratory and anxiety related behaviors were also assessed. In vehicle-treated rats, exposure to a modified version of the familiar environment was associated with an increase of numerical densities of Fos-immunoreactive nuclei in sectors CA1 and CA2, while exposure to a completely novel environment was associated with an increase in sectors CA1, CA4, and DG, compared with the familiar environment. Pharmacological disruption of amygdala activity resulted in a failure to increase Fos induction in the hippocampus in response to these environments. Exploratory behavior in response to the different environments was not altered by manipulation of amygdala activity. These findings support the idea that the amygdala modulates spatial information processing in the hippocampus and may affect encoding of specific environmental features, while complex behavioral responses to environment may be the result of broader neural circuits. These findings also raise the possibility that amygdala abnormalities may contribute to impairments in cognitive information processing in subjects with major psychoses. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 32 | Neuropsychopharmacology 2008 Mar 33: 933-45 |
| PMID | 17507910 |
| Title | Decreased mRNA expression of netrin-G1 and netrin-G2 in the temporal lobe in schizophrenia and bipolar disorder. |
| Abstract | The membrane-bound axon guidance molecules netrin-G1 (NTNG1) and netrin-G2 (NTNG2) play a role in synaptic formation and maintenance. Non-coding single nucleotide polymorphisms (SNPs) in both genes have been reported to be associated with schizophrenia. The main aim of this study was to determine if NTNG1 and NTNG2 mRNA expression is altered in schizophrenia or bipolar disorder, and/or influenced by disease-associated SNPs. NTNG1 and NTNG2 mRNAs were examined in the medial and inferior temporal lobe using in situ hybridization and RT-PCR in the Stanley Medical Research Institute array collection, and in rat hippocampus during development and after antipsychotic administration. NTNG1 mRNA isoforms were also examined during human brain development. For NTNG1, the G1c isoform was reduced in bipolar disorder and with a similar trend in schizophrenia; expression of four other NTNG1 isoforms was unchanged. In both schizophrenia and bipolar disorder, NTNG2 mRNA was reduced in CA3, with reductions also found in CA4 and perirhinal cortex in bipolar disorder. The SNPs did not affect NTNG1 or NTNG2 mRNA expression. Both NTNG1 and NTNG2 mRNAs were developmentally regulated, and were unaltered by haloperidol, but NTNG2 mRNA was modestly increased by clozapine. These data implicate NTNG1 and NTNG2 in the pathophysiology of schizophrenia and bipolar disorder, but do not support the hypothesis that altered mRNA expression is the mechanism by which genetic variation of NTNG1 or NTNG2 may confer disease susceptibility. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 33 | Acta Neuropathol. 2009 Apr 117: 395-407 |
| PMID | 18777029 |
| Title | Stereologic investigation of the posterior part of the hippocampus in schizophrenia. |
| Abstract | Structural magnetic resonance imaging and postmortem studies showed volume loss in the hippocampus in schizophrenia. The noted tissue reduction in the posterior section suggests that some cellular subfractions within this structure might be reduced in schizophrenia. To address this, we investigated numbers and densities of neurons, oligodendrocytes and astrocytes in the posterior hippocampal subregions in postmortem brains from ten patients with schizophrenia and ten matched controls using design-based stereology performed on Nissl-stained sections. Compared to the controls, the patients with schizophrenia showed a significant decrease in the mean number of oligodendrocytes in the left and right CA4. This is the first finding of reduced numbers of oligodendrocytes in CA4 of the posterior part of the hippocampus in schizophrenia. Our results are in line with earlier findings in the literature concerning decreased numbers of oligodendrocytes in the prefrontal cortex in schizophrenia. Our results may indicate disturbed connectivity of the CA4 of the posterior part of the hippocampus in schizophrenia and, thus, contribute to the growing number of studies showing the involvement of posterior hippocampal pathology in the pathophysiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 34 | Br. J. Pharmacol. 2009 May 157: 118-29 |
| PMID | 19413576 |
| Title | Altered histamine H3 receptor radioligand binding in post-mortem brain samples from subjects with psychiatric diseases. |
| Abstract | Histamine is a modulatory neurotransmitter in the brain. Auto- and hetero-histamine H3 receptors are present in human brain and are potential targets of antipsychotics. These receptors may also display disease-related abnormalities in psychiatric disorders. Here we have assessed how histamine H3 receptors in human brain may be affected in schizophrenia, bipolar disorder, major depression. Histamine H3 receptor radioligand binding assays were applied to frozen post-mortem prefrontal and temporal cortical sections and anterior hippocampal sections from subjects with schizophrenia, bipolar disorder, major depression and matched controls. Compared with the controls, increased H3 receptor radioligand binding was found in dorsolateral prefrontal cortex of schizophrenic subjects (especially the ones who were treated with atypical antipsychotics), and bipolar subjects with psychotic symptoms. No differences in H3 receptor radioligand binding were found in the temporal cortex. In hippocampal formation of control subjects, H3 receptor radioligand binding was prominent in dentate gyrus, subiculum, entorhinal cortex and parasubiculum. Decreased H3 binding was found in the CA4 area of bipolar subjects. Decreased H3 binding in CA2 and presubiculum of medication-free bipolar subjects was also seen. The results suggest that histamine H3 receptors in the prefrontal cortex take part in the modulation of cognition, which is impaired in schizophrenic subjects and bipolar subjects with psychotic symptoms. Histamine H3 receptors probably regulate connections between hippocampus and various cortical and subcortical regions and could also be involved in the neuropathology of schizophrenia and bipolar disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 35 | Br. J. Pharmacol. 2009 May 157: 118-29 |
| PMID | 19413576 |
| Title | Altered histamine H3 receptor radioligand binding in post-mortem brain samples from subjects with psychiatric diseases. |
| Abstract | Histamine is a modulatory neurotransmitter in the brain. Auto- and hetero-histamine H3 receptors are present in human brain and are potential targets of antipsychotics. These receptors may also display disease-related abnormalities in psychiatric disorders. Here we have assessed how histamine H3 receptors in human brain may be affected in schizophrenia, bipolar disorder, major depression. Histamine H3 receptor radioligand binding assays were applied to frozen post-mortem prefrontal and temporal cortical sections and anterior hippocampal sections from subjects with schizophrenia, bipolar disorder, major depression and matched controls. Compared with the controls, increased H3 receptor radioligand binding was found in dorsolateral prefrontal cortex of schizophrenic subjects (especially the ones who were treated with atypical antipsychotics), and bipolar subjects with psychotic symptoms. No differences in H3 receptor radioligand binding were found in the temporal cortex. In hippocampal formation of control subjects, H3 receptor radioligand binding was prominent in dentate gyrus, subiculum, entorhinal cortex and parasubiculum. Decreased H3 binding was found in the CA4 area of bipolar subjects. Decreased H3 binding in CA2 and presubiculum of medication-free bipolar subjects was also seen. The results suggest that histamine H3 receptors in the prefrontal cortex take part in the modulation of cognition, which is impaired in schizophrenic subjects and bipolar subjects with psychotic symptoms. Histamine H3 receptors probably regulate connections between hippocampus and various cortical and subcortical regions and could also be involved in the neuropathology of schizophrenia and bipolar disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 36 | J Neural Transm (Vienna) 2009 Dec 116: 1657-65 |
| PMID | 19823762 |
| Title | Increased D-amino acid oxidase expression in the bilateral hippocampal CA4 of schizophrenic patients: a post-mortem study. |
| Abstract | An important risk gene in schizophrenia is D-: amino acid oxidase (DAAO). To establish if expression of DAAO is altered in cortical, hippocampal or thalamic regions of schizophrenia patients, we measured gene expression of DAAO in a post-mortem study of elderly patients with schizophrenia and non-affected controls in both hemispheres differentiating between gray and white matter. We compared cerebral post-mortem samples (granular frontal cortex BA9, middle frontal cortex BA46, superior temporal cortex BA22, entorhinal cortex BA28, sensoric cortex BA1-3, hippocampus (CA4), mediodorsal nucleus of the thalamus) from 10 schizophrenia patients to 13 normal subjects investigating gene expression of DAAO in the gray and white matter of both hemispheres of the above-mentioned brain regions by in situ-hybridization. We found increased expression of DAAO-mRNA in the hippocampal CA4 of schizophrenic patients. Compared to the control group, both hemispheres of the hippocampus of schizophrenic patients showed an increased expression of 46% (right, P = 0.013) and 54% (left, P = 0.019), respectively. None of the other regions examined showed statistically significant differences in DAAO expression. This post-mortem study demonstrated increased gene expression of DAAO in the left and right hippocampus of schizophrenia patients. This increased expression could be responsible for a decrease in local D-: serine levels leading to a NMDA-receptor hypofunction that is hypothesized to play a major role in the pathophysiology of schizophrenia. However, our study group was small and results should be verified using larger samples. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 37 | J Neural Transm (Vienna) 2009 Dec 116: 1657-65 |
| PMID | 19823762 |
| Title | Increased D-amino acid oxidase expression in the bilateral hippocampal CA4 of schizophrenic patients: a post-mortem study. |
| Abstract | An important risk gene in schizophrenia is D-: amino acid oxidase (DAAO). To establish if expression of DAAO is altered in cortical, hippocampal or thalamic regions of schizophrenia patients, we measured gene expression of DAAO in a post-mortem study of elderly patients with schizophrenia and non-affected controls in both hemispheres differentiating between gray and white matter. We compared cerebral post-mortem samples (granular frontal cortex BA9, middle frontal cortex BA46, superior temporal cortex BA22, entorhinal cortex BA28, sensoric cortex BA1-3, hippocampus (CA4), mediodorsal nucleus of the thalamus) from 10 schizophrenia patients to 13 normal subjects investigating gene expression of DAAO in the gray and white matter of both hemispheres of the above-mentioned brain regions by in situ-hybridization. We found increased expression of DAAO-mRNA in the hippocampal CA4 of schizophrenic patients. Compared to the control group, both hemispheres of the hippocampus of schizophrenic patients showed an increased expression of 46% (right, P = 0.013) and 54% (left, P = 0.019), respectively. None of the other regions examined showed statistically significant differences in DAAO expression. This post-mortem study demonstrated increased gene expression of DAAO in the left and right hippocampus of schizophrenia patients. This increased expression could be responsible for a decrease in local D-: serine levels leading to a NMDA-receptor hypofunction that is hypothesized to play a major role in the pathophysiology of schizophrenia. However, our study group was small and results should be verified using larger samples. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 38 | J Psychiatry Neurosci 2011 May 36: 195-203 |
| PMID | 21223646 |
| Title | Decreased BDNF, trkB-TK+ and GAD67 mRNA expression in the hippocampus of individuals with schizophrenia and mood disorders. |
| Abstract | Brain-derived neurotrophic factor (BDNF), tyrosine kinase receptor (trkB-TK+) and glutamic acid decarboxylase (GAD67) mRNA levels have previously been found to be reduced in the prefrontal cortex of patients with schizophrenia. To determine whether this reduction extends to other brain regions, we measured the expression levels of BDNF, trkB-TK+ and GAD67 mRNA in regions of the hippocampus, including the dentate gyrus (DG), cornu ammonis subfields (CA1-4), subiculum and entorhinal cortex (EC) of individuals with schizophrenia, bipolar disorder, major depression and unaffected controls. In situ hybridization was performed on postmortem brain tissue obtained from the Stanley Foundation Consortium and analyzed using film-based quantification. Analyses of covariance comparing the expression of mRNA among all groups revealed a significant decrease in BDNF mRNA in CA4 in the bipolar disorder group compared with controls (33%). We found trkB-TK+ mRNA levels to be significantly reduced in CA4 in the schizophrenia group (36%) and in layer II of the EC in the bipolar disorder and major depression groups (28%, 21%, respectively) compared with controls. In addition, GAD67 mRNA levels were reduced in patients with schizophrenia in both the DG (23%) and CA4 (60%) compared with controls. Individuals with major depression also expressed significantly less GAD67 mRNA (44%) compared with controls in CA4 of the hippocampus. It is necessary to account for factors that influence the molecular preservation in postmortem brain tissue, including pH, postmortem interval and tissue storage time. Moreover, there are limitations to the sensitivity of the film-based method of quantification. Our findings show abnormal BDNF, trkB-TK+ and GAD67 mRNA expression in the hippocampus of individuals with schizophrenia and mood disorders, indicating that fundamental properties of hippocampal signalling transmission, plasticity and circuitry may be affected in individuals with these major mental illnesses. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 39 | Neuropsychobiology 2012 -1 66: 57-62 |
| PMID | 22797278 |
| Title | Decreased reelin expression in the left prefrontal cortex (BA9) in chronic schizophrenia patients. |
| Abstract | Reelin is under epigenetic control and has been reported to be decreased in cortical regions in schizophrenia. To establish if expression of reelin is altered in specific cortical, hippocampal or thalamic regions of schizophrenia patients, we measured gene expression of reelin in a postmortem study of elderly patients with schizophrenia and non-affected controls in both hemispheres differentiating between gray and white matter. We compared cerebral postmortem samples (dorsolateral prefrontal cortex BA9 and BA46, superior temporal cortex BA22, entorhinal cortex BA28, sensoric cortex BA1-3, hippocampus, CA4, mediodorsal nucleus of the thalamus) from 12 schizophrenia patients with 13 normal subjects investigating gene expression of reelin in the gray and white matter of both hemispheres by in situ-hybridization. The left prefrontal area (BA9) of schizophrenia patients revealed a decreased expression of reelin-mRNA of 29.1% in the white (p = 0.022) and 13.6% in the gray matter (p = 0.007) compared to the control group. None of the other regions examined showed any statistically significant differences. Since reelin is responsible for migration and synapse formation, the decreased gene expression of reelin in the left prefrontal area of schizophrenia patients points to neurodevelopmental deficits in neuronal migration and synaptic plasticity. However, our study group was small, and results should be verified using larger samples. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 40 | Neuroreport 2013 Nov 24: 928-33 |
| PMID | 24045778 |
| Title | Expression of presynaptic markers in a neurodevelopmental animal model with relevance to schizophrenia. |
| Abstract | Administration of N-methyl-D-aspartate receptor antagonist phencyclidine (PCP) to rat pups at postnatal day (PND) 7, 9, and 11 [neonatal PCP (neoPCP) model] induces cognitive deficits similar to those observed in schizophrenia. Expression of presynaptic SNARE protein, synaptosomal-associated protein of 25 kDa (Snap25), has been shown to be downregulated in postmortem brains from patients with schizophrenia. The present study was designed to investigate the long-term effects of neoPCP administration on expression of presynaptic markers altered in schizophrenia. Using radioactive in-situ hybridization, the expression of Snap25 was measured in the prefrontal cortex and the hippocampal formation (CA1, CA3, CA4, and dentate gyrus) at PND 29 and 80 in neoPCP and control rats. As a secondary presynaptic marker, the expressional level of synaptophysin was also measured in the same areas. Stereological estimation of the number of neurons and volume was used to exclude potential bias in cell numbers. A significant reduction in the expression of Snap25 in the hippocampal CA4 region was observed in adult neoPCP rats (PND 80, P<0.01), but not in preadolescent rats (PND 29), indicating a late developmental manifestation of a presynaptic pathology. The number of neurons and volume of the CA4 region showed no change in PCP rats compared with the controls. Furthermore, expression of another presynaptic marker, synaptophysin, remained unaffected by the PCP treatment. These findings indicate that perinatal PCP injections induce a delayed presynaptic impact on the vesicle fusion machinery in a brain region important for cognitive processes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 41 | Brain Behav. Immun. 2013 Aug 32: 51-62 |
| PMID | 23395714 |
| Title | Expression of immune genes on chromosome 6p21.3-22.1 in schizophrenia. |
| Abstract | schizophrenia is a common mental illness with a large genetic component. Three genome-wide association studies have implicated the major histocompatibility complex gene region on chromosome 6p21.3-22.1 in schizophrenia. In addition, nicotine, which is commonly abused in schizophrenia, affects the expression of central nervous system immune genes. Messenger RNA levels for genes in the 6p21.3-22.1 region were measured in human postmortem hippocampus of 89 subjects. The effects of schizophrenia diagnosis, smoking and systemic inflammatory illness were compared. Cell-specific expression patterns for the class I major histocompatibility complex gene HLA-A were explored utilizing in situ hybridization. Expression of five genes was altered in schizophrenic subjects. Messenger RNA levels for the class I major histocompatibility complex antigen HLA-B were increased in schizophrenic nonsmokers, while levels for smokers were indistinguishable from those of controls. ?2 microglobulin, HLA-A and Notch4 were all expressed in a pattern where inflammatory illness was associated with increased expression in controls but not in subjects with schizophrenia. schizophrenia was also associated with increased expression of Butyrophilin 2A2. HLA-A was expressed in glutamatergic and GABAergic neurons in the dentate gyrus, hilus, and the stratum pyramidale of the CA1-CA4 regions of the hippocampus, but not in astrocytes. In conclusion, the expression of genes from the major histocompatibility complex region of chromosome 6 with likely roles in synaptic development is altered in schizophrenia. There were also significant interactions between schizophrenia diagnosis and both inflammatory illness and smoking. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 42 | Brain Behav. Immun. 2013 Aug 32: 51-62 |
| PMID | 23395714 |
| Title | Expression of immune genes on chromosome 6p21.3-22.1 in schizophrenia. |
| Abstract | schizophrenia is a common mental illness with a large genetic component. Three genome-wide association studies have implicated the major histocompatibility complex gene region on chromosome 6p21.3-22.1 in schizophrenia. In addition, nicotine, which is commonly abused in schizophrenia, affects the expression of central nervous system immune genes. Messenger RNA levels for genes in the 6p21.3-22.1 region were measured in human postmortem hippocampus of 89 subjects. The effects of schizophrenia diagnosis, smoking and systemic inflammatory illness were compared. Cell-specific expression patterns for the class I major histocompatibility complex gene HLA-A were explored utilizing in situ hybridization. Expression of five genes was altered in schizophrenic subjects. Messenger RNA levels for the class I major histocompatibility complex antigen HLA-B were increased in schizophrenic nonsmokers, while levels for smokers were indistinguishable from those of controls. ?2 microglobulin, HLA-A and Notch4 were all expressed in a pattern where inflammatory illness was associated with increased expression in controls but not in subjects with schizophrenia. schizophrenia was also associated with increased expression of Butyrophilin 2A2. HLA-A was expressed in glutamatergic and GABAergic neurons in the dentate gyrus, hilus, and the stratum pyramidale of the CA1-CA4 regions of the hippocampus, but not in astrocytes. In conclusion, the expression of genes from the major histocompatibility complex region of chromosome 6 with likely roles in synaptic development is altered in schizophrenia. There were also significant interactions between schizophrenia diagnosis and both inflammatory illness and smoking. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 43 | J Psychiatr Res 2014 Dec 59: 14-21 |
| PMID | 25246365 |
| Title | Interplay between childhood trauma and BDNF val66met variants on blood BDNF mRNA levels and on hippocampus subfields volumes in schizophrenia spectrum and bipolar disorders. |
| Abstract | Here we investigated a two hit gene environment model in relation to functional genomic factors (BDNF mRNA), and volume of hippocampal subfields in schizophrenia spectrum and bipolar disorders, focusing on both an environmental (childhood trauma) and genetic risk factor (BDNF val66met). A total of 323 patients with a broad DSM-IV schizophrenia spectrum disorder or bipolar disorder were consecutively recruited. A history of childhood trauma was obtained using the Childhood Trauma Questionnaire. BDNF DNA and RNA were analyzed using standardized procedures. A subsample of n = 108 underwent MRI scanning, and the FreeSurfer was used to obtain measures of hippocampal subfield. All MRI data were corrected for age and gender, with post-hoc analysis correcting for ICV. A history of childhood trauma or being a met carrier of the BDNF val66met was associated with significantly reduced BDNF mRNA level. Additive effects were observed between a history of childhood trauma and BDNF val66met, in the direction of met carriers with high levels of childhood trauma having the lowest BDNF mRNA levels. Lastly, met carriers reporting high levels of childhood trauma (specifically sexual or physical abuse) had significantly reduced hippocampal subfield volumes CA2/3 and CA4 dentate gyrus. The current findings demonstrate that the reduced BDNF mRNA levels found in psychosis may be associated with both a history of childhood trauma and BDNF val66met variants. Further, our study supports a two hit model including a history of childhood trauma as well as genetic vulnerability (met carriers of the BDNF val66met) behind reduced volume of hippocampal subfields in psychosis. This was specifically found for areas important for neurogenesis, the CA2/3 and the CA4 DG. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 44 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2014 Jan 48: 295-303 |
| PMID | 23313563 |
| Title | Is there an association between peripheral immune markers and structural/functional neuroimaging findings? |
| Abstract | There is mounting evidence that inflammatory processes play a key role in emotional as well as cognitive dysfunctions. In this context, research employing magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MR spectroscopy) suggests a possible link between structural/functional anomalies in the brain and an increase of circulating inflammation markers. The present paper reviews this research, with particular focus on major depressive disorder (MDD), cognitive impairment in older adults, Alzheimer's disease (AD) and schizophrenia. In MDD, cognitive impairment and AD, inflammatory processes have been found to be associated with both structural and functional anomalies, perhaps under the influence of environmental stress. Not enough research can suggest similar considerations in schizophrenia, although studies in mice and non-human primates support the belief that inflammatory responses generated during pregnancy can affect brain development and contribute to the etiology of schizophrenia. The present review suggests a link between inflammatory processes and MRI detected anomalies in the brain of individuals with MDD, older adults with cognitive impairment as well as of individuals with AD and schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 45 | Biol. Psychiatry 2015 Mar 77: 581-8 |
| PMID | 25127742 |
| Title | In vivo hippocampal subfield volumes in schizophrenia and bipolar disorder. |
| Abstract | Hippocampal dysfunction and volume reductions have been reported in patients with schizophrenia and bipolar disorder. The hippocampus consists of anatomically distinct subfields. We investigated to determine whether in vivo volumes of hippocampal subfields differ between clinical groups and healthy control subjects. Clinical examination and magnetic resonance imaging were performed in 702 subjects (patients with schizophrenia spectrum [n = 210; mean age, 32.0 ± 9.3 (SD) years; 59% male], patients with bipolar spectrum [n = 192; mean age, 35.5 ± 11.5 years; 40% male] and healthy control subjects [n = 300; mean age, 35.3 ± 9.9 years; 53% male]). Hippocampal subfield volumes were estimated with FreeSurfer. General linear models were used to explore diagnostic differences in hippocampal subfield volumes, covarying for age, intracranial volume, and medication. Post hoc analyses of associations to psychosis symptoms (Positive and Negative Syndrome Scale) and cognitive function (verbal memory [California Verbal Learning Test, second edition] and IQ [Wechsler Abbreviated Scale of Intelligence]) were performed. Patient groups had smaller cornu ammonis (CA) subfields CA2/3 (left, p = 7.2 × 10(-6); right, p = 2.3 × 10(-6)), CA4/dentate gyrus (left, p = 1.4 × 10(-5); right, p = 2.3 × 10(-6)), subiculum (left, p = 3.7 × 10(-6); right, p = 2.8 × 10(-8)), and right CA1 (p = .006) volumes than healthy control subjects, but smaller presubiculum volumes were found only in patients with schizophrenia (left, p = 6.7 × 10(-5); right, p = 1.6 × 10(-7)). Patients with schizophrenia had smaller subiculum (left, p = .035; right, p = .031) and right presubiculum (p = .002) volumes than patients with bipolar disorder. Smaller subiculum volumes were related to poorer verbal memory in patients with bipolar disorder and healthy control subjects and to negative symptoms in patients with schizophrenia. Hippocampal subfield volume reductions are found in patients with schizophrenia and bipolar disorder. The magnitude of reduction is greater in patients with schizophrenia, particularly in the hippocampal outflow regions presubiculum and subiculum. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 46 | PLoS ONE 2015 -1 10: e0117785 |
| PMID | 25658118 |
| Title | Hippocampal subfield volumes in first episode and chronic schizophrenia. |
| Abstract | Reduced hippocampal volume in schizophrenia is a well-replicated finding. New imaging techniques allow delineation of hippocampal subfield volumes. Studies including predominantly chronic patients demonstrate differences between subfields in sensitivity to illness, and in associations with clinical features. We carried out a cross-sectional and longitudinal study of first episode, sub-chronic, and chronic patients, using an imaging strategy that allows for the assessment of multiple hippocampal subfields. Hippocampal subfield volumes were measured in 34 patients with schizophrenia (19 first episode, 6 sub-chronic, 9 chronic) and 15 healthy comparison participants. A subset of 10 first episode and 12 healthy participants were rescanned after six months. Total left hippocampal volume was smaller in sub-chronic (p = 0.04, effect size 1.12) and chronic (p = 0.009, effect size 1.42) patients compared with healthy volunteers. The CA2-3 subfield volume of chronic patients was significantly decreased (p = 0.009, effect size 1.42) compared to healthy volunteers. The CA4-DG volume was significantly reduced in all three patient groups compared to healthy group (all p < 0.005). The two affected subfield volumes were inversely correlated with severity of negative symptoms (p < 0.05). There was a small, but statistically significant decline in left CA4-DG volume over the first six months of illness (p = 0.01). Imaging strategies defining the subfields of the hippocampus may be informative in linking symptoms and structural abnormalities, and in understanding more about progression during the early phases of illness in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 47 | Front Cell Neurosci 2016 -1 10: 78 |
| PMID | 27065804 |
| Title | Oligodendrocyte and Interneuron Density in Hippocampal Subfields in Schizophrenia and Association of Oligodendrocyte Number with Cognitive Deficits. |
| Abstract | In schizophrenia, previous stereological post-mortem investigations of anterior, posterior, and total hippocampal subfields showed no alterations in total neuron number but did show decreased oligodendrocyte numbers in CA4, an area that corresponds to the polymorph layer of the dentate gyrus (DG). However, these investigations identified oligodendrocytes only on the basis of morphological criteria in Nissl staining and did not assess alterations of interneurons with immunohistochemical markers. Moreover, the association of findings in the posterior hippocampus with cognitive deficits remains unknown. On the basis of the available clinical records, we compared patients with definite and possible cognitive dysfunction; nine patients had evidence in their records of either definite (n = 4) or possible (n = 5) cognitive dysfunction. Additionally, we assessed the density of two oligodendrocyte subpopulations immunostained by the oligodendrocyte transcription factors Olig1 and Olig2 and of interneurons immunolabeled by parvalbumin. We investigated posterior hippocampal subregions in the post-mortem brains of the same schizophrenia patients (SZ; n = 10) and healthy controls (n = 10) we examined in our previously published stereological studies. Our stereological studies found that patients with definite cognitive deficits had decreased total/Nissl-stained oligodendrocyte numbers in the left (p = 0.014) and right (p = 0.050) CA4, left CA2/3 (p = 0.050), left CA1 (p = 0.027), and left (p = 0.050) and right (p = 0.014) subiculum of the anterior part of the hippocampus compared to patients with possible cognitive deficits. In the present study, we found no significant influence of definite cognitive deficits in the posterior part of the hippocampus, whereas in the entire hippocampus SZ with definite cognitive deficits showed decreased oligodendrocyte numbers in the left (p = 0.050) and right (p = 0.050) DG and left CA2/3 (p = 0.050). We did not find significant differences in Olig1-, Olig2-, or parvalbumin-positive cell density between SZ and controls in any of the subregions of the posterior hippocampus. Based on the results from our stereological study we hypothesize that a decreased number of oligodendrocytes in the anterior and entire hippocampus may be involved in cognitive deficits by impairing the connectivity of this structure in schizophrenia. In the posterior hippocampus, we could not replicate previously reported findings of decreased interneurons from the entire hippocampus. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |