Relationship between somatostatin and death receptor expression in the orbital frontal cortex in schizophrenia: a postmortem brain mRNA study

Abstract

Recently, we provided evidence showing reductions in GAD67 and Dlx mRNAs in the orbital frontal cortex (OFC) in schizophrenia. It is unknown whether these reductions relate mainly to somatostatin (SST) or parvalbumin (PV) mRNA expression changes, and/or whether these reductions are related to decreased SST mRNA+ interneuron density. To determine whether inhibitory interneuron deficits in the OFC from people with schizophrenia are greatest for SST or PV mRNAs, and whether any such deficits relate to mRNAs encoding cell death signalling molecules. Inhibitory interneuron mRNAs (SST; PV: in situ hybridization, quantitative PCR (qPCR)) and death signaling mRNAs [FAS receptor (FASR); TNFSF13: qPCR] were measured in control and schizophrenia subjects (38/38). SST mRNA+ interneuron-like cells were quantified in layer II in the gyrus rectus. Gray matter SST and PV mRNAs were correlated with interstitial white matter neuron (IWMN) density (GAD65/67; NeuN) and death signaling mRNAs. SST mRNA was reduced in OFC layers I–VI in schizophrenia (both in situ and qPCR), with greatest deficit in layer II (67%). Layer II SST mRNA+ neuron density was reduced in schizophrenia (~29%). PV mRNA was reduced in layers III (18%) and IV (31%) with no significant diagnostic difference in PV mRNA measured by qPCR. FASR mRNA was increased in schizophrenia (34%). SST, but not PV, expression correlated negatively with FASR and TNFSF13 expressions and with IWMN density. Our study demonstrates that SST interneurons are predominantly linked to the inhibitory interneuron pathology in the OFC in schizophrenia and that increased death receptor signaling mRNAs relate to prominent laminar deficits in SST mRNA in the OFC in schizophrenia. We suggest that SST interneurons may be more vulnerable to increased death receptor signaling than PV interneurons. Increases in cell death markers has been linked to the demise of cortical neurons in the social brain areas of people with schizophrenia. Schizophrenia has been previously linked to defects in the orbital frontal cortex (OFC) – a part of the brain important for using emotion to motivate decisions, and for effective social behavior. This report finds that people with schizophrenia have reduced levels of mRNAs found in two types of interneurons: somatostatin and parvalbumin; both types can inhibit the activity of other neurons. Using postmortem examinations of brains from 38 schizophrenia patients and 38 control subjects, Cyndi Shannon Weickert and co-workers at Neuroscience Research Australia observed that a shortfall in somatostatin mRNA related closely to increased activity other molecules putatively involved in programmed cell death – apoptosis. This suggests somatostatin neurons may be vulnerable to apoptosis in people with schizophrenia and suggests that greater examination of this possibility is needed.