Title - Feature Finding
Feature Finding Figure
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 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 (Figure). Laminar and cellular level analyses revealed that lower SSTR2 mRNA levels were localized to pyramidal cells in the cortical layers 5-6. Levels of SSTR2 mRNA were lower in monkeys exposed chronically to low dose haloperidol, but no differences were observed in monkeys exposed to higher doses of haloperidol or to olanzapine or between subjects with schizophrenia on or off antipsychotic medications at the time of death. These findings suggest that lower SST mRNA expression in schizophrenia is accompanied by reduced levels of SSTR2 mRNA selectively in pyramidal neurons in layers 5-6. Together, these findings suggest converging pre- and post-synaptic mechanisms to reduce inhibitory inputs to pyramidal neurons in the infragranular layers of the DLPFC.
Beneyto M, Morris HM, Rovensky KC, Lewis DA: Lamina- and cell-specific alterations in cortical somatostatin receptor 2 expression in schizophrenia. Neuropharmacology, in press.

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David A. Lewis, M.D. | Department of Psychiatry | University of Pittsburgh
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