Cell-specific abnormalities of glutamate transporters in schizophrenia: sick astrocytes and compensating relay neurons?

Excitatory amino-acid transporters (EAATs) bind and transport glutamate, limiting spillover from synapses due to their dense perisynaptic expression primarily on astroglia. Converging evidence suggests that abnormalities in the astroglial glutamate transporter localization and function may underlie a disease mechanism with pathological glutamate spillover as well as alterations in the kinetics of perisynaptic glutamate buffering and uptake contributing to dysfunction of thalamo-cortical circuits in schizophrenia. We explored this hypothesis by performing cell- and region-level studies of EAAT1 and EAAT2 expression in the mediodorsal nucleus of the thalamus in an elderly cohort of subjects with schizophrenia. We found decreased protein expression for the typically astroglial-localized glutamate transporters in the mediodorsal and ventral tier nuclei. We next used laser-capture microdissection and quantitative polymerase chain reaction to assess cell-level expression of the transporters and their splice variants. In the mediodorsal nucleus, we found lower expression of transporter transcripts in a population of cells enriched for astrocytes, and higher expression of transporter transcripts in a population of cells enriched for relay neurons. We confirmed expression of transporter protein in neurons in schizophrenia using dual-label immunofluorescence. Finally, the pattern of transporter mRNA and protein expression in rodents treated for 9 months with antipsychotic medication suggests that our findings are not due to the effects of antipsychotic treatment. We found a compensatory increase in transporter expression in neurons that might be secondary to a loss of transporter expression in astrocytes. These changes suggest a profound abnormality in astrocyte functions that support, nourish and maintain neuronal fidelity and synaptic activity.

Molecular systems evaluation of oligomerogenic APP(E693Q) and fibrillogenic APP(KM670/671NL)/PSEN1(Δexon9) mouse models identifies shared features with human Alzheimer's brain molecular pathology.

Identification and characterization of molecular mechanisms that connect genetic risk factors to initiation and evolution of disease pathophysiology represent major goals and opportunities for improving therapeutic and diagnostic outcomes in Alzheimer's disease (AD). Integrative genomic analysis of the human AD brain transcriptome holds potential for revealing novel mechanisms of dysfunction that underlie the onset and/or progression of the disease. We performed an integrative genomic analysis of brain tissue-derived transcriptomes measured from two lines of mice expressing distinct mutant AD-related proteins. The first line expresses oligomerogenic mutant APP(E693Q) inside neurons, leading to the accumulation of amyloid beta (Aß) oligomers and behavioral impairment, but never develops parenchymal fibrillar amyloid deposits. The second line expresses APP(KM670/671NL)/PSEN1(Δexon9) in neurons and accumulates fibrillar Aß amyloid and amyloid plaques accompanied by neuritic dystrophy and behavioral impairment. We performed RNA sequencing analyses of the dentate gyrus and entorhinal cortex from each line and from wild-type mice. We then performed an integrative genomic analysis to identify dysregulated molecules and pathways, comparing transgenic mice with wild-type controls as well as to each other. We also compared these results with datasets derived from human AD brain. Differential gene and exon expression analysis revealed pervasive alterations in APP/Aß metabolism, epigenetic control of neurogenesis, cytoskeletal organization and extracellular matrix (ECM) regulation. Comparative molecular analysis converged on FMR1 (Fragile X Mental Retardation 1), an important negative regulator of APP translation and oligomerogenesis in the post-synaptic space. Integration of these transcriptomic results with human postmortem AD gene networks, differential expression and differential splicing signatures identified significant similarities in pathway dysregulation, including ECM regulation and neurogenesis, as well as strong overlap with AD-associated co-expression network structures. The strong overlap in molecular systems features supports the relevance of these findings from the AD mouse models to human AD.

Myelination, oligodendrocytes, and serious mental illness.

Historically, the human brain has been conceptually segregated from the periphery and further dichotomized into gray matter (GM) and white matter (WM) based on the whitish appearance of the exceptionally high lipid content of the myelin sheaths encasing neuronal axons. These simplistic dichotomies were unfortunately extended to conceptually segregate neurons from glia, cognition from behavior, and have been codified in the separation of clinical and scientific fields into medicine, psychiatry, neurology, pathology, etc. The discrete classifications have helped obscure the importance of continual dynamic communication between all brain cell types (neurons, astrocytes, microglia, oligodendrocytes, and precursor (NG2) cells) as well as between brain and periphery through multiple signaling systems. The signaling systems range from neurotransmitters to insulin, angiotensin, and multiple kinases such a glycogen synthase kinase 3 (GSK-3) that together help integrate metabolism, inflammation, and myelination processes and orchestrate the development, plasticity, maintenance, and repair that continually optimize function of neural networks. A more comprehensive, evolution-based, systems biology approach that integrates brain, body, and environmental interactions may ultimately prove more fruitful in elucidating the complexities of human brain function. The historic focus on neurons/GM is rebalanced herein by highlighting the importance of a systems-level understanding of the interdependent age-related shifts in both central and peripheral homeostatic mechanisms that can lead to remarkably prevalent and devastating neuropsychiatric diseases. Herein we highlight the role of glia, especially the most recently evolved oligodendrocytes and the myelin they produce, in achieving and maintaining optimal brain function. The human brain undergoes exceptionally protracted and pervasive myelination (even throughout its GM) and can thus achieve and maintain the rapid conduction and synchronous timing of neural networks on which optimal function depends. The continuum of increasing myelin vulnerability resulting from the human brain's protracted myelination underlies underappreciated communalities between different disease phenotypes ranging from developmental ones such as schizophrenia (SZ) and bipolar disorder (BD) to degenerative ones such as Alzheimer's disease (AD). These shared vulnerabilities also expose significant yet underexplored opportunities for novel treatment and prevention approaches that have the potential to considerably reduce the tremendous burden of neuropsychiatric disease.

Gene expression signature is shared by patients with Alzheimer's disease and schizophrenia at the superior temporal gyrus.

BACKGROUND: Alzheimer's disease and Schizophrenia are two common diseases of the brain with significant differences in neuropathology, etiology and symptoms. This dissimilarity in the two diseases makes a comparison of the two ideal for detecting molecular substrates that are common to brain disorders in general. METHODS: In this study, we compared gene expression profiles across multiple brain areas, taken postmortem from patients with well-characterized Alzheimer's disease and Schizophrenia, and from cognitively normal control group with no neuro- or psychopathology. RESULTS: Although the totality of gene expression changes in the two diseases is dissimilar, a subset of genes appears to play a role in both diseases in specific brain regions. We find at Brodmann area 22, the superior temporal gyrus, a statistically significant number of genes with apparently disregulated expression in both diseases. Furthermore, we found genes that differentiate the two diseases from the control across multiple brain regions, and note that these genes were usually down-regulated. Brodmann area 8, part of the superior frontal cortex, is relatively abundant with them. CONCLUSION: We show overwhelming statistical evidence for Alzheimer's and Schizophrenia sharing a specific molecular background at the superior temporal gyrus. We suggest that impairment of the regulation of autophagy pathway is shared, in BA 22, by the two diseases.

Increased serotonin 2C receptor mRNA editing: a possible risk factor for suicide.

Suicide is a major public health problem with approximately 1 million victims each year worldwide. Up to 90% of adults who commit suicide have at least one psychiatric diagnosis such as major depression, bipolar disorder (BPD), schizophrenia (SZ), substance abuse or dependence. A question that has remained unanswered is whether the biological substrates of suicide are distinct from those of the psychiatric disorders in which it occurs. The serotonin 2C receptor (5-HT 2C R) has been implicated in depression and suicide. We, therefore, compared the frequencies of its mRNA editing variants in postmortem prefrontal cortical specimens from subjects who committed suicide or who died from other causes. All suicides occurred in the context of either SZ or BPD. The non-suicide cases included subjects with either SZ or BPD as well as subjects with no psychiatric diagnosis. We identified 5-HT 2CR mRNA editing variations that were associated with suicide but not with the comorbid psychiatric diagnoses, and were not influenced by demographic characteristics (age and sex) and alcohol or drug use. These variations consisted of a significant increase in the pool of mRNA variants (ACD and ABCD) that encode one of the most prevalent and highly edited isoforms of 5-HT 2C R, that is, VSV (Val156-Ser158-Val160). Because the VSV isoform of 5-HT 2C R exhibits low functional activity, an increase in its expression frequency may significantly influence the serotonergic regulation of the brain. Thus, at least in patients with SZ or BPD, overexpression of the VSV isoform in the prefrontal cortex may represent an additional risk factor for suicidal behavior.

Emergence of interoceptive and exteroceptive control of behavior in rats.

The role of exteroceptive and interoceptive aversive stimuli in rats 2 to 14 days old was investigated according to an odor aversion paradigm. Amyl acetate odor was paired with eigher peripheral shock, intraperitoneal shock, or lithium chloride poisoning. Intraperitoneal shock was an effective unconditioned stimulus at all ages and produced odor aversions comparable to lithium chloride poisoning; peripheral shock, however, was effective only in rats 10 days of age or older. Interoceptive control of aversively motivated behaviors thus seems to develop before exteroceptive control, and the failure of previous studies to find reliable learning and retention of shock-motivated behaviors before 8 to 10 days of age may be attributable to the site to which shock was applied rather than to insensitivity to shock per se.

Parahippocampal gyrus expression of endothelial and insulin receptor signaling pathway genes is modulated by Alzheimer's disease and normalized by treatment with anti-diabetic agents.

A large body of literature links risk of cognitive decline, mild cognitive impairment (MCI) and dementia with Type 2 Diabetes (T2D) or pre-diabetes. Accumulating evidence implicates a close relationship between the brain insulin receptor signaling pathway (IRSP) and the accumulation of amyloid beta and hyperphosphorylated and conformationally abnormal tau. We showed previously that the neuropathological features of Alzheimer's disease (AD were reduced in patients with diabetes who were treated with insulin and oral antidiabetic medications. To understand better the neurobiological substrates of T2D and T2D medications in AD, we examined IRSP and endothelial cell markers in the parahippocampal gyrus of controls (N = 30), of persons with AD (N = 19), and of persons with AD and T2D, who, in turn, had been treated with anti-diabetic drugs (insulin and or oral agents; N = 34). We studied the gene expression of selected members of the IRSP and selective endothelial cell markers in bulk postmortem tissue from the parahippocampal gyrus and in endothelial cell enriched isolates from the same brain region. The results indicated that there are considerable abnormalities and reductions in gene expression (bulk tissue homogenates and endothelial cell isolates) in the parahippocampal gyri of persons with AD that map directly to genes associated with the microvasculature and the IRSP. Our results also showed that the numbers of abnormally expressed microvasculature and IRSP associated genes in diabetic AD donors who had been treated with anti-diabetic agents were reduced significantly. These findings suggest that anti-diabetic treatments may reduce or normalize compromised microvascular and IRSP functions in AD.

Quantitative analysis of glutamate transporter mRNA expression in prefrontal and primary visual cortex in normal and schizophrenic brain.

Abnormalities of the glutamatergic system in schizophrenia have been identified in numerous studies, but little is known about the role of glutamate transporters and their messenger RNA (mRNA) expression. In addition, the abundances of the two major isoforms of human excitatory amino acid transporter 2 (EAAT2) or its rat ortholog, glutamate transporter 1, have never been compared in a quantitative manner. Using quantitative reverse transcription-polymerase chain reaction, we established that the expression of the EAAT1, EAAT2a, EAAT2b, and EAAT3 transcripts was not different in the dorsolateral prefrontal and primary visual cortices of persons with schizophrenia relative to matched controls. EAAT2a expression was about 25-fold and 10-fold higher than EAAT2b in human and rat brain, respectively. The data provided no evidence of an effect of antipsychotic medications on the mRNA expression of the glutamate transporters. However, because most of the schizophrenic subjects in the cohort had been treated with antipsychotics for many years, it is still possible that changes in transporter expression were masked by medication effects.

Extracellular Tau Oligomers Produce An Immediate Impairment of LTP and Memory.

Non-fibrillar soluble oligomeric forms of amyloid-ß peptide (oAß) and tau proteins are likely to play a major role in Alzheimer's disease (AD). The prevailing hypothesis on the disease etiopathogenesis is that oAß initiates tau pathology that slowly spreads throughout the medial temporal cortex and neocortices independently of Aß, eventually leading to memory loss. Here we show that a brief exposure to extracellular recombinant human tau oligomers (oTau), but not monomers, produces an impairment of long-term potentiation (LTP) and memory, independent of the presence of high oAß levels. The impairment is immediate as it raises as soon as 20 min after exposure to the oligomers. These effects are reproduced either by oTau extracted from AD human specimens, or naturally produced in mice overexpressing human tau. Finally, we found that oTau could also act in combination with oAß to produce these effects, as sub-toxic doses of the two peptides combined lead to LTP and memory impairment. These findings provide a novel view of the effects of tau and Aß on memory loss, offering new therapeutic opportunities in the therapy of AD and other neurodegenerative diseases associated with Aß and tau pathology.

Variations in differential gene expression patterns across multiple brain regions in schizophrenia.

Large-scale gene expression studies in schizophrenia (SZ) have generally focused on the dorsolateral prefrontal cortex. Despite a wealth of evidence implicating multiple other brain regions in the disease, studies of other brain regions have been less frequent and have rarely been performed in the same subjects. We analyzed postmortem gene expression in the frontal, cingulate, temporal, parietal and occipital cortices (Brodmann areas 8, 10, 44, 46, 23/31, 24/32, 20, 21, 22, 36/28, 7 and 17, respectively) as well as in the hippocampus, caudate nucleus and putamen of persons with schizophrenia and control subjects (N's = 13) using Affymetrix GeneChip microarrays. Under identical data filtering conditions, the superior temporal cortex (BA22) of schizophrenia subjects showed the maximal number of altered transcripts (approximately 1200) compared to controls. Anterior and posterior cingulate cortices (BA23/31, 24/32) and the hippocampus followed the superior temporal cortex with two-times lower numbers of altered transcripts. The dorsolateral prefrontal cortex (BA46), a frequent target of SZ-associated studies, showed substantially fewer altered transcripts (approximately 33). These regional differences in differentially expressed genes could not be accounted for by factors such as total numbers of genes expressed or the filtering conditions and criteria used for identification of differentially expressed genes. These findings suggest that the temporal and cingulate cortices and the hippocampal formation represent brain regions of particular abnormality in SZ and may be more susceptible to the disease process(es) than other regions thus far studied.

Increased concentrations of presynaptic proteins in the cingulate cortex of subjects with schizophrenia.

BACKGROUND: Cytoarchitectural and neurochemical studies demonstrate disorganization in the cerebral cortex in schizophrenia, which perhaps underlies the severe behavioral disturbances of the disease. This neuronal disarray should be accompanied by synaptic abnormalities. As such, presynaptic proteins have proved valuable indexes of synaptic density and their concentrations have correlated markedly with synaptic loss. Our study sought to determine whether abnormalities exist in the concentrations of presynaptic proteins in the postmortem cerebral cortex of subjects with schizophrenia. METHODS: Presynaptic protein immunoreactivities were assessed in 4 different cerebrocortical regions derived from 16 elderly controls, 19 elderly subjects with schizophrenia, and 24 subjects with Alzheimer's disease. Tissues were assayed with the monoclonal antibodies EP10 and SP4, which recognize synaptophysin, and the monoclonal antibodies SP6 and SP14, which detect syntaxin and synaptosomal-associated protein-25-kd immunoreactivities, respectively. RESULTS: In subjects with schizophrenia relative to controls, presynaptic proteins were increased in the cingulate cortex, but were unchanged in the temporal, frontal, and parietal cortices. In contrast, when cases with Alzheimer's disease were compared with controls, presynaptic proteins were decreased in the frontal, temporal, and parietal samples. CONCLUSIONS: These findings reveal changes in the synaptic organization of the cingulate cortex in schizophrenia relative to other areas examined. These changes are distinct from the deficits in presynaptic proteins observed in Alzheimer's disease.

Dopamine receptor transcript expression in striatum and prefrontal and occipital cortex. Focal abnormalities in orbitofrontal cortex in schizophrenia.

BACKGROUND: The identification of novel subtypes of the dopamine receptors has renewed interest in the involvement of dopaminergic mechanisms in schizophrenia. We determined the expression of transcripts encoding the dopamine receptors in the brains of schizophrenic patients. METHODS: The levels of the messenger RNA molecules encoding the 5 dopamine receptors were quantified in postmortem brain samples from 16 schizophrenic patients and 9 control subjects. Samples from multiple regions of the prefrontal cortex, primary visual cortex, and striatum were subjected to in situ hybridization followed by quantitative image analysis. RESULTS: Expression of dopamine receptor transcripts did not differ between schizophrenic patients and controls in striatum or visual cortex. Dramatic decreases of dopamine receptor transcripts were found in the prefrontal cortex, but these changes were restricted to the D3 and D4 receptors, and localized to Brodmann area 11 (orbitofrontal cortex). CONCLUSIONS: Cortical dopaminergic neurotransmission may be disrupted in schizophrenia at the level of receptor expression. There appears to be a focal abnormality of D3 and D4 messenger RNA expression in the prefrontal cortex, with down-regulation of both, consistent with prefrontal cortical hypodopaminergia in schizophrenia.

Alzheimer disease and related neurodegenerative diseases in elderly patients with schizophrenia: a postmortem neuropathologic study of 100 cases.

BACKGROUND: Clinical studies suggest that severe cognitive impairment is common among elderly patients with schizophrenia who reside in long-stay psychiatric institutions; however, previous autopsy-based neuropathologic investigations have provided conflicting results about the occurrence of Alzheimer disease (AD) in elderly patients with schizophrenia. We report the results of a comprehensive neuropathologic study performed to identify AD and other dementing neurodegenerative diseases in elderly patients with schizophrenia. METHODS: A neuropathologic examination was performed on 100 consecutive autopsy brain specimens of patients aged 52 to 101 years (mean, 76.5 years). A cognitive assessment of these cases was also done by employing the Clinical Dementia Rating Scale. For comparison, we included 47 patients with nonschizophrenic psychiatric disorders from the same psychiatric hospital and 50 age-matched control subjects. RESULTS: Although 72% of the patients with schizophrenia showed cognitive impairment, AD was diagnosed in only 9% of the patients and other dementing diseases were diagnosed in only 4% of the patients. The degree of senile plaques or neurofibrillary tangles was not different in the group with schizophrenia compared with the age-matched controls or the group with nonschizophrenic psychiatric disorders. The higher Clinical Dementia Rating Scale scores lacked correlation with neuropathologic evidence of dementing disorders. In the 87 cases lacking a neuropathologic diagnosis of AD or other dementing disorders, the mean (+/-SD) Clinical Dementia Rating Scale score was 2.21 (+/-1.14), with 43 of the cases scoring 3 or higher (indicating severe, profound, or terminal cognitive impairment). CONCLUSIONS: This study provides evidence that elderly patients with schizophrenia are not inordinately prone to the development of AD or to increased senile plaques or neurofibrillary tangle formation in the brain. Other dementing neurodegenerative disorders are also uncommon. The cognitive impairment in elderly patients with schizophrenia must, therefore, be related to some alternative mechanisms.

Neuropeptide abnormalities in patients with early Alzheimer disease.

BACKGROUND: Deficits in somatostatin-like immunoreactivity (SLI) and corticotropin-releasing factor immunoreactivity (CRF-IR) are well recognized as prominent neurochemical deficits in Alzheimer disease (AD). The question of whether these profound neuropeptidergic deficits found in patients with end-stage disease extend into those with much earlier disease is relatively unanswered. To determine the relation between level of SLI and CRF-IR in different cerebrocortical regions to the earliest signs of cognitive deterioration in AD. METHODS: We examined SLI and CRF-IR levels in 9 neocortical brain regions of 66 elderly patients in a postmortem study of nursing home residents who had either no significant neuropathologic lesions or lesions associated only with AD. Patients were assessed by the Clinical Dementia Rating scale (CDR) to have no dementia or questionable, mild, or moderate dementia, and were compared with 15 patients with severe dementia. RESULTS: Both CRF-IR and SLI were significantly reduced in the cortices of patients with the most severe dementia, but only the levels of CRF-IR were reduced in those with mild (CDR = 1.0) and moderate dementia (CDR = 2.0). Levels of CRF-IR and SLI correlated significantly with CDR, but this correlation was more robust for CRF-IR and persisted even when severely cognitively impaired patients were eliminated from analysis. CONCLUSIONS: Although SLI and CRF-IR levels are significantly reduced in patients with severe dementia, only CRF-IR is reduced significantly in the cortices of those with mild dementia. Thus, CRF-IR can serve as a potential neurochemical marker of early dementia and possibly early AD.

Integration of gene expression and GWAS results supports involvement of calcium signaling in Schizophrenia.

The number of Genome Wide Association Studies (GWAS) of schizophrenia is rapidly growing. However, the small effect of individual genes limits the number of reliably implicated genes, which are too few and too diverse to perform reliable pathway analysis; hence the biological roles of the genes implicated in schizophrenia are unclear. To overcome these limitations we combine GWAS with genome-wide expression data from human post-mortem brain samples of schizophrenia patients and controls, taking these steps: 1) Identify 36 GWAS-based genes which are expressed in our dataset. 2) Find a cluster of 19 genes with highly correlated expression. We show that this correlation pattern is robust and statistically significant. 3) GO-enrichment analysis of these 19 genes reveals significant enrichment of ion channels and calcium-related processes. This finding (based on analyzing a small number of coherently expressed genes) is validated and enhanced in two ways: First, the emergence of calcium channels and calcium signaling is corroborated by identifying proteins that interact with those encoded by the cluster of 19. Second, extend the 19 cluster genes into 1028 genes, whose expression is highly correlated with the cluster's average profile. When GO-enrichment analysis is performed on this extended set, many schizophrenia related pathways appear, with calcium-related processes enriched with high statistical significance. Our results give further, expression-based validation to GWAS results, support a central role of calcium-signaling in the pathogenesis of schizophrenia, and point to additional pathways potentially related to the disease.

Abnormal subcellular localization of GABAA receptor subunits in schizophrenia brain.

Inhibitory neurotransmission is primarily mediated by γ-aminobutyric acid (GABA) activating synaptic GABA type A receptors (GABA(A)R). In schizophrenia, presynaptic GABAergic signaling deficits are among the most replicated findings; however, postsynaptic GABAergic deficits are less well characterized. Our lab has previously demonstrated that although there is no difference in total protein expression of the α1-6, ß1-3 or γ2 GABA(A)R subunits in the superior temporal gyrus (STG) in schizophrenia, the α1, ß1 and ß2 GABA(A)R subunits are abnormally N-glycosylated. N-glycosylation is a posttranslational modification that has important functional roles in protein folding, multimer assembly and forward trafficking. To investigate the impact that altered N-glycosylation has on the assembly and trafficking of GABA(A)Rs in schizophrenia, this study used western blot analysis to measure the expression of α1, α2, ß1, ß2 and γ2 GABA(A)R subunits in subcellular fractions enriched for endoplasmic reticulum (ER) and synapses (SYN) from STG of schizophrenia (N = 16) and comparison (N = 14) subjects and found evidence of abnormal localization of the ß1 and ß2 GABA(A)R subunits and subunit isoforms in schizophrenia. The ß2 subunit is expressed as three isoforms at 52 kDa (ß2(52 kDa)), 50 kDa (ß2(50 kDa)) and 48 kDa (ß2(48 kDa)). In the ER, we found increased total ß2 GABA(A)R subunit (ß2(ALL)) expression driven by increased ß2(50 kDa), a decreased ratio of ß(248 kDa):ß2(ALL) and an increased ratio of ß2(50 kDa):ß2(48 kDa). Decreased ratios of ß1:ß2(ALL) and ß1:ß2(50 kDa) in both the ER and SYN fractions and an increased ratio of ß2(52 kDa):ß(248 kDa) at the synapse were also identified in schizophrenia. Taken together, these findings provide evidence that alterations of N-glycosylation may contribute to GABAergic signaling deficits in schizophrenia by disrupting the assembly and trafficking of GABA(A)Rs.

Glutamate transporter splice variant expression in an enriched pyramidal cell population in schizophrenia.

Dysregulation of the glutamate transporters EAAT1 and EAAT2 and their isoforms have been implicated in schizophrenia. EAAT1 and EAAT2 expression has been studied in different brain regions but the prevalence of astrocytic glutamate transporter expression masks the more subtle changes in excitatory amino acid transporters (EAATs) isoforms in neurons in the cortex. Using laser capture microdissection, pyramidal neurons were cut from the anterior cingulate cortex of postmortem schizophrenia (n = 20) and control (n = 20) subjects. The messenger RNA (mRNA) levels of EAAT1, EAAT2 and the splice variants EAAT1 exon9skipping, EAAT2 exon9skipping and EAAT2b were analyzed by real time PCR (RT-PCR) in an enriched population of neurons. Region-level expression of these transcripts was measured in postmortem schizophrenia (n = 25) and controls (n = 25). The relationship between selected EAAT polymorphisms and EAAT splice variant expression was also explored. Anterior cingulate cortex pyramidal cell expression of EAAT2b mRNA was increased (P < 0.001; 67%) in schizophrenia subjects compared with controls. There was no significant change in other EAAT variants. EAAT2 exon9skipping mRNA was increased (P < 0.05; 38%) at region level in the anterior cingulate cortex with no significant change in other EAAT variants at region level. EAAT2 single-nucleotide polymorphisms were significantly associated with changes in EAAT2 isoform expression. Haloperidol decanoate-treated animals, acting as controls for possible antipsychotic effects, did not have significantly altered neuronal EAAT2b mRNA levels. The novel finding that EAAT2b levels are increased in populations of anterior cingulate cortex pyramidal cells further demonstrates a role for neuronal glutamate transporter splice variant expression in schizophrenia.

Levels of mRNAs encoding synaptic vesicle and synaptic plasma membrane proteins in the temporal cortex of elderly schizophrenic patients.

BACKGROUND: Electron microscopy and biochemical studies indicate that developmental abnormalities in synaptic organization may be present in brains of schizophrenic patients. This study determined whether these synaptic abnormalities are reflected in differential or uniform alterations in the expression of various synaptic protein genes in the left superior temporal gyrus of schizophrenic patients. METHODS: Levels of mRNAs encoding four synaptic vesicle proteins (synaptotagmin I [p65], rab3a, synaptobrevin 1, and synaptobrevin 2) and two synaptic plasma membrane proteins (syntaxin 1A and SNAP-25) were measured postmortem in the left superior temporal gyrus from elderly (58-95 years) schizophrenic patients (n = 14) and age-matched control subjects (n = 9). RESULTS: There were significant negative correlations between age and levels of synaptotagmin I (p65), rab3a, synaptobrevin 1, SNAP-25, and syntaxin 1A mRNAs in schizophrenic patients (-.692 < r < -.517,.003 < p <.030) but not in control subjects. Levels of all six synaptic mRNAs studied were increased in the younger (58-79 years) subgroup of schizophrenic patients compared to control subjects and older (80-95 years) subgroup of schizophrenic patients. CONCLUSIONS: That similar abnormalities were found for mRNAs encoding different synaptic vesicle and synaptic plasma membrane proteins suggests that they reflect overall neurodevelopmental abnormalities in synaptic connectivity in the temporal cortex of schizophrenic patients rather than changes in the number of synaptic vesicles per synapse or abnormalities in a specific synaptic function.