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Lamina- and cell-specific alterations in cortical somatostatin receptor 2 mRNA expression in schizophrenia.

ABSTRACT: Disturbed cortical ?-aminobutyric acid (GABA) neurotransmission in schizophrenia is evident from lamina- and cell type- specific alterations in presynaptic markers. In the dorsolateral prefrontal cortex (DLPFC), these alterations include lower transcript expression of glutamic acid decarboxylase (GAD67) and somatostatin (SST), a neuropeptide expressed in the Martinotti subpopulation of GABA neurons whose axons innervate the distal apical dendrites of pyramidal neurons. However, whether the alterations in SST-containing interneurons are associated with changes in post-synaptic receptors for SST has not been examined. Thus, we used in situ hybridization to quantify the mRNA expression levels of SST receptors subtype 1 (SSTR1) and subtype 2 (SSTR2) in DLPFC area 9 from 23 matched pairs of subjects with schizophrenia and normal comparison subjects. We also assessed the effects of potential confounding variables within the human subjects and in brain specimens from macaque monkeys with long term exposure to antipsychotic drugs. SSTR1 mRNA levels did not differ between subject groups. In contrast, mean cortical SSTR2 mRNA levels were significantly 19% lower in the subjects with schizophrenia. Laminar and cellular level analyses revealed that lower SSTR2 mRNA levels were localized to pyramidal cells in cortical layers 5-6. Expression of SSTR2 mRNA did not differ between monkeys exposed chronically to high doses of haloperidol or olanzapine and control animals, or between subjects with schizophrenia on or off antipsychotic medications at the time of death. However, levels of SSTR2 mRNA were significantly 37.6% lower in monkeys exposed chronically to low dose haloperidol, suggesting that the lower levels of SSTR2 mRNA selectively in pyramidal neurons in DLPFC layers 5-6 in schizophrenia should be interpreted with caution. In concert with prior findings of lower SST mRNA expression in the same subjects, the results of this study suggest the convergence of pre- and post-synaptic mechanisms to reduce inhibitory inputs to pyramidal neurons in the infragranular layers of the DLPFC.

SUBMITTER: Beneyto M

PROVIDER: S-EPMC3096699 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Lamina- and cell-specific alterations in cortical somatostatin receptor 2 mRNA expression in schizophrenia.

Beneyto Monica M Morris Harvey M HM Rovensky Katherine C KC Lewis David A DA

Neuropharmacology 20110105 3

Disturbed cortical γ-aminobutyric acid (GABA) neurotransmission in schizophrenia is evident from lamina- and cell type- specific alterations in presynaptic markers. In the dorsolateral prefrontal cortex (DLPFC), these alterations include lower transcript expression of glutamic acid decarboxylase (GAD67) and somatostatin (SST), a neuropeptide expressed in the Martinotti subpopulation of GABA neurons whose axons innervate the distal apical dendrites of pyramidal neurons. However, whether the alter ...[more]

PMID: 21215273

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Project description:The brain-derived neurotrophic factor (BDNF) gene contains multiple 5' promoters which generate alternate transcripts. Previously, we found that pan-BDNF mRNA and protein are reduced in the dorsolateral prefrontal cortex (DLPFC) from patients with schizophrenia. In this study, we determined which of the four most abundant and best characterized BDNF alternate transcripts, I-IX, II-IX, IV-IX, and VI-IX are altered in schizophrenia. Using a cohort from the NIMH, USA, we found that BDNF II-IX mRNA was significantly reduced in the DLPFC of patients with schizophrenia, and we replicated this finding using a second cohort from Sydney, Australia. Moreover, we show that BDNF protein expression [including prepro ( approximately 32 kDa), pro ( approximately 28 kDa) and mature ( approximately 14 kDa) BDNF] is reduced in the DLPFC of patients with schizophrenia. We next determined the regional specificity of the BDNF mRNA reduction by measuring BDNF transcripts in the parietal cortex and hippocampus and found no significant changes. The effect of antipsychotics on BDNF alternate transcript expression was also examined and we found no relationship between BDNF mRNA expression and antipsychotic use. As schizophrenic patients are often prescribed antidepressants which can up-regulate expression of BDNF, we investigated the relationship between antidepressant treatment and BDNF transcript expression. All four BDNF transcripts were significantly up-regulated in schizophrenic patients treated with antidepressants. Moreover, we found significant reductions in BDNF transcripts II-IX and IV-IX in the parietal cortex and VI-IX in the hippocampus of patients with schizophrenia who did not have a history of treatment with antidepressants. This suggests that down-regulation of at least one out of four major BDNF transcripts occurs in various brain regions of patients with schizophrenia, particularly in the DLPFC which appears to have the most robust BDNF deficit in schizophrenia.

Dataset Information

Lamina- and cell-specific alterations in cortical somatostatin receptor 2 mRNA expression in schizophrenia.

Publications

Lamina- and cell-specific alterations in cortical somatostatin receptor 2 mRNA expression in schizophrenia.

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