Brain Regions Of Schizophrenic Patients Research Articles

A role for zinc transporter gene SLC39A12 in the nervous system and beyond.

The SLC39A12 gene encodes the zinc transporter protein ZIP12, which is expressed across many tissues and is highly abundant in the vertebrate nervous system. As a zinc transporter, ZIP12 functions to transport zinc across cellular membranes, including cellular zinc influx across the plasma membrane. Genome-wide association and exome sequencing studies have shown that brain susceptibility-weighted magnetic resonance imaging (MRI) intensity is associated with ZIP12 polymorphisms and rare mutations. ZIP12 is required for neural tube closure and embryonic development in Xenopus tropicalis. Frog embryos depleted of ZIP12 by antisense morpholinos develop an anterior neural tube defect and lack viability. ZIP12 is also necessary for neurite outgrowth and mitochondrial function in mouse neural cells. ZIP12 mRNA is increased in brain regions of schizophrenic patients. Outside of the nervous system, hypoxia induces ZIP12 expression in multiple mammalian species, including humans, which leads to endothelial and smooth muscle thickening in the lung and contributes towards pulmonary hypertension. Other studies have associated ZIP12 with other diseases such as cancer. Given that ZIP12 is highly expressed in the brain and that susceptibility-weighted MRI is associated with brain metal content, ZIP12 may affect neurological diseases and psychiatric illnesses such as Parkinson's disease, Alzheimer's disease, and schizophrenia. Furthermore, the induction of ZIP12 and resultant zinc uptake under pathophysiological conditions may be a critical component of disease pathology, such as in pulmonary hypertension. Drug compounds that bind metals like zinc may be able to treat diseases associated with impaired zinc homeostasis and altered ZIP12 function.

Overexpression of complement component C4 in the dorsolateral prefrontal cortex, parietal cortex, superior temporal gyrus and associative striatum of patients with schizophrenia

BackgroundIn schizophrenia, abnormal synaptic pruning during adolescence may be due to altered expression of the Complement component 4 (C4). Overexpression of C4 genes has been identified in the total cerebral cortex and in 6 different brain regions of schizophrenic patients compared to controls. These alterations should be replicated and extended to other brain regions relevant to schizophrenia. Moreover, it remains unknown whether cerebral and peripheral C4 expression levels are related. MethodsWe explored C4 genes expression both at the cerebral and peripheral levels. Using shinyGEO application we analyzed C4 expression from eight Gene Expression Omnibus datasets obtained from 196 schizophrenic patients and 182 control subjects. First, we compared C4 expression between schizophrenic patients and controls in postmortem cerebral samples from 7 different brain regions. Then, we compared C4 expression between schizophrenic patients and controls in 4 peripheral tissues. ResultsAt the cerebral level, we provide further evidence of C4 overexpression in schizophrenic patients. Consistently with a previous report, we found C4 overexpression in the dorsolateral prefrontal cortex and in the parietal cortex of schizophrenic patients. The observation of C4 overexpression was further extended to the superior temporal cortex and the associative striatum of schizophrenic patients. Conversely, no significant alteration of C4 expression was observed in peripheral tissues. ConclusionsOur results support the hypothesis of an excessive Complement activity in various brain regions of schizophrenic patients which may disrupt the synaptic pruning process occurring during adolescence. C4 overexpression may be specific to the cerebral tissue while other alterations of the Complement system may be detected at the systemic level.

Ventral medial prefrontal functional connectivity and emotion regulation in chronic schizophrenia: A pilot study

People with schizophrenia exhibit impaired social cognitive functions, particularly emotion regulation. Abnormal activations of the ventral medial prefrontal cortex (vMPFC) during emotional tasks have been demonstrated in schizophrenia, suggesting its important role in emotion processing in patients. We used the resting-state functional connectivity approach, setting a functionally relevant region, the vMPFC, as a seed region to examine the intrinsic functional interactions and communication between the vMPFC and other brain regions in schizophrenic patients. We found hypo-connectivity between the vMPFC and the medial frontal cortex, right middle temporal lobe (MTL), right hippocampus, parahippocampal cortex (PHC) and amygdala. Further, there was a decreased strength of the negative connectivity (or anticorrelation) between the vMPFC and the bilateral dorsal lateral prefrontal cortex (DLPFC) and pre-supplementary motor areas. Among these connectivity alterations, reduced vMPFC-DLPFC connectivity was positively correlated with positive symptoms on the Positive and Negative Syndrome Scale, while vMPFC-right MTL/PHC/amygdala functional connectivity was positively correlated with the performance of emotional regulation in patients. These findings imply that communication and coordination throughout the brain networks are disrupted in schizophrenia. The emotional correlates of vMPFC connectivity suggest a role of the hypo-connectivity between these regions in the neuropathology of abnormal social cognition in chronic schizophrenia.

Neuroanatomical Circuitry Associated with Exploratory Eye Movement in Schizophrenia: A Voxel-Based Morphometric Study

Schizophrenic patients present abnormalities in a variety of eye movement tasks. Exploratory eye movement (EEM) dysfunction appears to be particularly specific to schizophrenia. However, the underlying mechanisms of EEM dysfunction in schizophrenia are not clearly understood. To assess the potential neuroanatomical substrates of EEM, we recorded EEM performance and conducted a voxel-based morphometric analysis of gray matter in 33 schizophrenic patients and 29 well matched healthy controls. In schizophrenic patients, decreased responsive search score (RSS) and widespread gray matter density (GMD) reductions were observed. Moreover, the RSS was positively correlated with GMD in distributed brain regions in schizophrenic patients. Furthermore, in schizophrenic patients, some brain regions with neuroanatomical deficits overlapped with some ones associated with RSS. These brain regions constituted an occipito-tempro-frontal circuitry involved in visual information processing and eye movement control, including the left calcarine cortex [Brodmann area (BA) 17], the left cuneus (BA 18), the left superior occipital cortex (BA 18/19), the left superior frontal gyrus (BA 6), the left cerebellum, the right lingual cortex (BA 17/18), the right middle occipital cortex (BA19), the right inferior temporal cortex (BA 37), the right dorsolateral prefrontal cortex (BA 46) and bilateral precentral gyri (BA 6) extending to the frontal eye fields (FEF, BA 8). To our knowledge, we firstly reported empirical evidence that gray matter loss in the occipito-tempro-frontal neuroanatomical circuitry of visual processing system was associated with EEM performance in schizophrenia, which may be helpful for the future effort to reveal the underlying neural mechanisms for EEM disturbances in schizophrenia.

Schizophrenia: Redox Regulation and Volume Neurotransmission

Here, we show that volume neurotransmission and the redox property of dopamine, as well as redox-regulated processes at glutamate receptors, can contribute significantly to our understanding of schizophrenia. Namely, volume neurotransmission may play a key role in the development of dysconnectivity between brain regions in schizophrenic patients, which can cause abnormal modulation of NMDA-dependent synaptic plasticity and produce local paroxysms in deafferented neural areas. During synaptic transmission, neuroredox regulations have fundamental functions, which involve the excellent antioxidant properties and nonsynaptic neurotransmission of dopamine. It is possible that the effect of redox-linked volume neurotransmission (diffusion) of dopamine is not as exact as communication by the classical synaptic mechanism, so approaching the study of complex schizophrenic mechanisms from this perspective may be beneficial. However, knowledge of redox signal processes, including the sources and molecular targets of reactive species, is essential for understanding the physiological and pathophysiological signal pathways in cells and the brain, as well as for pharmacological design of various types of new drugs.

S29-03 How hormones influence gene expression: Implications to the pathophysiology of schizophrenia

Schizophrenia is a complex genetic disorder. The lack of concordance on disease manifestation in monozygotic twins provides clear evidence that environmental factors are key determinants in disease aetiology. In accordance, various environmental modulators such as hormones and vitamins may well contribute to the altered expression pattern of several genes identified in post-mortem brain tissue of patients. We constructed a microarray platform containing 1,808 human genes, where 142 belong to vitamin A, thyroid hormone and estrogens’ metabolic pathways, to specifically address whether these could contribute to a molecular signature of schizophrenia in peripheral lymphocytes. We found that the genes encoding for PLP1, UGT1A6, NTRK1, THRAP1, ESR2, TRIP13, MAPK8, TGFB2, IGFBP4 are differentially expressed in lymphocytes of patients under treatment with clozapine, risperdal or haloperidol. Some of these genes have been previously reported by others to be altered in brain regions of schizophrenic patients, and all are implicated in pathways suggested to be involved in the disease. These observations further support that:1.studies in peripheral blood lymphocytes may contribute to reveal candidate genes in schizophrenia;2.transcription modulation of several genes may occur through the mediation of vitamin and hormones, therefore linking genes and environment in schizophrenia.In order to understand the involvement of these genes in schizophrenia, future studies should investigate whether some of the observed changes are replicated in animal models of the disease, and how antipsychotic treatment interferes with their expression.

Association study of polymorphisms in the mitochondrial aspartate/glutamate carrier SLC25A12 (aralar) gene with schizophrenia

Aralar is a mitochondrial calcium-regulated aspartate-glutamate carrier mainly distributed in brain and skeletal muscle, and involved in the transport of aspartate from mitochondria to the cytosol of a cell. Studies have shown that the brain N-acetyl aspartate (NAA) levels are greatly decreased in aralar-deficient mice, suggesting that aralar plays an important role in the synthesis of NAA in neuronal cells. Since magnetic resonance spectroscopy studies have revealed consistently reduced NAA levels in various brain regions of schizophrenic patients and their unaffected relatives, genes that affect aralar levels or NAA metabolism in the brain may be implicated in the pathogenesis of schizophrenia. Aralar is encoded by the SLC25A12 gene. In the past this gene has been found to be associated with susceptibility to autism; in this study we tested the hypothesis that SLC25A12 genetic variants confer susceptibility to schizophrenia. Six SLC25A12 polymorphisms were studied in a sample population of 253 people with schizophrenia and 216 normal controls. Significant linkage disequilibrium was obtained among the six polymorphisms. However, neither single marker nor haplotype analysis revealed an association between variants at the SLC25A12 locus and schizophrenia, suggesting that it is unlikely that the SLC25A12 polymorphisms investigated play a substantial role in conferring susceptibility to schizophrenia in the Chinese population. Further studies with SLC25A12 variants relating to brain NAA levels in patients with schizophrenia are suggested.

Promoter analysis of human glutamate carboxypeptidase II

The expression of glutamate carboxypeptidase II (GCP II) is reduced in selective brain regions in schizophrenic patients. To investigate transcriptional mechanisms regulating the human GCP II gene, a 3460 bp DNA fragment comprised of the proximal 3228 bp of 5′ untranscribed sequence and first 232 bp of 5′ UTR portion of this gene was cloned into the mammalian luciferase reporter gene vector pGL3-Basic. Transfection assays in human astrocyte-derived SVG and human prostate tumor-derived LNCaP cells demonstrated that constructs with 3460, 1590 and 761 bp portions of 5′ region of human GCP II gene were able to drive the luciferase reporter gene. Additional deletion constructs showed that in the SVG cell line, constructs with 511 and 411 bp of GCP II gene fragments yielded highest transcriptional activity, with declining activity upon further removal of 5′ sequences. 15 bp of the promoter 5′ to a 225 bp GCP II fragment were essential for luciferase expression. Thus, in the SVG cells, the proximal 240 bp of the human GCP II promoter (232 bp of the 5′ UTR and 8 bp of 5′ untranscribed sequences) may represent the core promoter. Further, while a LyF-1 site lies within and overlaps a transcription start site in the 15 bp sequence, site-directed mutagenesis shows that LyF-1 is not the transcription initiator for the “TATA and CAAT” box lacking GCP II gene in the SVG cells. Finally, pattern differences in GCP II gene promoter expression in SVG and LNCaP cells suggest that sequences beyond 240 bp may be important for tissue-specific GCP II expression.

3′ UTR (AGG) n repeat of glial cell line-derived neurotrophic factor (GDNF) gene polymorphism in schizophrenia

Association studies on gene polymorphisms of neurotransmitter systems have hypothesized an involvement of dopamine receptors in susceptibility to schizophrenia. However, structural and morphological abnormalities in different brain regions of schizophrenic patients support neurodevelopmental etiology for schizophrenia and neurotrophic factor genes could be candidates for genetic studies. The glial cell line-derived neurotrophic factor (GDNF) is a neurotrophic and potential differentiation factor for dopaminergic systems. We have performed, in an Italian sample, an association study on 3′ UTR (AGG) n repeat in GDNF gene. Our results have evidenced a difference in the allele frequencies between patients and controls (CLUMP (T1) χ 2=17.365, df=9, P=0.043) and the (AGG) n ≥15 alleles (Fisher Exact Test (two side) χ 2=11.818, df=1, P=0.0003) were more present in the controls group. Similarity, the carriers of (AGG) n ≥15 (OR=0.176 95% CI: 0.060–0.520) were more present in the same group. These results support that the (AGG) n ≥15 alleles could be protective factors against schizophrenia and thus they suggest a possible involvement of GDNF gene in the genetic liability to illness.

No Evidence of Altered In Vivo Benzodiazepine Receptor Binding in Schizophrenia

Deficits in gamma-amino-butyric acid (GABA) neurotransmitter systems have been implicated in the pathophysiology of schizophrenia for more than two decades. Previous postmortem and in vivo studies of benzodiazepine (BDZ) receptor density have reported alterations in several brain regions of schizophrenic patients. The goal of this study was to better characterize possible alterations of the in vivo regional distribution volume (VT) of BDZ receptors in schizophrenia, using the selective BDZ antagonist [123I]iomazenil and single photon emission computerized tomography (SPECT). Regional BDZ VT was measured under sustained radiotracer equilibrium conditions. The reproducibility and reliability of this measurement was established in four healthy volunteers. No differences in regional BDZ VT were observed between 16 male schizophrenic patients and 16 matched controls. No relationships were observed between BDZ VT and severity of psychotic symptoms in any of the regions examined. In conclusion, this study failed to identify alterations of BDZ receptors density in schizophrenia. If this illness is associated with deficits in GABA transmission, these deficits do not substantially involve BDZ receptor expression or regulation.

Erratum to ``MRI T 2 relaxation times of brain regions in schizophrenic patients and control subjects'' [Psychiatry Res. Neuroimaging 75 (1997) 173

The publisher regrets that an error occurred in the abstract of the above article. The abstract is reprinted below, with words that were inadvertently omitted indicated in bold-faced type. In this MRI investigation T 2 relaxation times were studied in schizophrenic patients compared to normal control subjects. Approximate T 2 relaxation times were calculated using signal intensity at two echo times in several brain regions of 25 male schizophrenic patients and 25 age-matched, normal male control subjects. The schizophrenic patients showed significantly longer T 2 relaxation times as compared to normal control subjects in the left anterior column of the fornix. This is a small structure, prone to partial volume effects and this may account for these findings. There was a trend towards longer T 2 times in the left frontal cortex and shorter T 2 times in right temporal cortex in schizophrenic patients as compared to control subjects. There were right/left differences in relaxation times within each group. In both patients and control subjects, frontal lobe white matter T 2 was longer on the right than on the left side. This finding is probably due to brain asymmetry and unrelated to the presence or absence of psychiatric illness. In schizophrenic patients only the left temporal cortex showed longer T 2 times than the right side. This observation could indicate left sided temporal lobe pathology in schizophrenia. © 1998 Elsevier Science Ireland Ltd.

MRI T 2 relaxation times of brain regions in schizophrenic patients and control subjects

In this MRI investigation T 2 relaxation times were studied in schizophrenic patients compared to normal control subjects. Approximate T 2 relaxation times were calculated using signal intensity at two echo times in several brain regions of 25 male schizophrenic patients and 25 age-matched, normal male control subjects. The schizophrenic patients showed significantly longer T 2 relaxation times as compared to normal control subjects in the left anterior column of the fornix. This is a small structure, prone to partial volume effects and this may account for these findings. There was a trend towards longer T 2 times in the left frontal cortex and right temporal cortex in schizophrenic patients as compared to control subjects. There were right/left differences in relaxation times within each group. In both patients and control subjects, frontal lobe white matter T 2 was longer on the right than on the left side. This finding is probably due to brain asymmetry and unrelated to the presence or absence of psychiatric illness. In schizophrenic patients only the left temporal cortex showed longer T 2 times than the right side. This observation could indicate left sided temporal lobe pathology in schizophrenia.

(3H]MK-801 binding sites in postmortem brain regions of schizophrenic patients

[3H]MK-801 binding was used as a marker for the NMDA receptorion channel complex in postmortem brain samples from the frontal cortex, hippocampus, putamen, entorhinal region, and amygdala of schizophrenic patients and controls. In schizophrenia [3H]MK-801 binding levels were increased in all brain regions investigated reaching significance in the putamen.

Altered relationships between metabolic rates of glucose in brain regions of schizophrenic patients.

Regional brain glucose metabolism was studied with positron emission tomography (PET) in healthy volunteers (n = 9) and schizophrenic patients (n = 15). The patients were in an acute phase of the disease and drug free. Cerebral metabolic rate with 11C-glucose as the tracer (CMRgl) was determined in both cortical and subcortical structures. In the healthy volunteers significant correlations were found between metabolic rates of some regions, but no relationships were found between CMRgl of limbic cortical areas and that of neocortical or subcortical structures. In the patients, high and significant positive correlations were found between metabolic rates in the neocortical areas, the limbic cortical areas and the subcortical areas. The results indicate differences in the neuronal interplay between regions of healthy and schizophrenic subjects. It is proposed that neuronal systems guiding the specificity and diversity in neuronal functions between different brain regions, are abnormal in schizophrenic patients. Such a disturbance may be the basis for the diversity of psychiatric symptoms in schizophrenics.

Quisqualate selectively inhibits a brain peptisade which cleaves N-acetyl-L-aspartyl-L-glutamate in vitro

The expression of glutamate carboxypeptidase II (GCP II) is reduced in selective brain regions in schizophrenic patients. To investigate transcriptional mechanisms regulating the human GCP II gene, a 3460 bp DNA fragment comprised of the proximal 3228 bp of 5′ untranscribed sequence and first 232 bp of 5′ UTR portion of this gene was cloned into the mammalian luciferase reporter gene vector pGL3-Basic. Transfection assays in human astrocyte-derived SVG and human prostate tumor-derived LNCaP cells demonstrated that constructs with 3460, 1590 and 761 bp portions of 5′ region of human GCP II gene were able to drive the luciferase reporter gene. Additional deletion constructs showed that in the SVG cell line, constructs with 511 and 411 bp of GCP II gene fragments yielded highest transcriptional activity, with declining activity upon further removal of 5′ sequences. 15 bp of the promoter 5′ to a 225 bp GCP II fragment were essential for luciferase expression. Thus, in the SVG cells, the proximal 240 bp of the human GCP II promoter (232 bp of the 5′ UTR and 8 bp of 5′ untranscribed sequences) may represent the core promoter. Further, while a LyF-1 site lies within and overlaps a transcription start site in the 15 bp sequence, site-directed mutagenesis shows that LyF-1 is not the transcription initiator for the “TATA and CAAT” box lacking GCP II gene in the SVG cells. Finally, pattern differences in GCP II gene promoter expression in SVG and LNCaP cells suggest that sequences beyond 240 bp may be important for tissue-specific GCP II expression.