Gene Expression Deficits in a Subclass of GABA Neurons in the Prefrontal Cortex of Subjects with Schizophrenia

Abstract

Markers of inhibitory neurotransmission are altered in the prefrontal cortex (PFC) of subjects with schizophrenia, and several lines of evidence suggest that these alterations may be most prominent in the subset of GABA-containing neurons that express the calcium-binding protein, parvalbumin (PV). To test this hypothesis, we evaluated the expression of mRNAs for PV, another calcium-binding protein, calretinin (CR), and glutamic acid decarboxylase (GAD67) in postmortem brain specimens from 15 pairs of subjects with schizophrenia and matched control subjects using single- and dual-label in situ hybridization. Signal intensity for PV mRNA expression in PFC area 9 was significantly decreased in the subjects with schizophrenia, predominantly in layers III and IV. Analysis at the cellular level revealed that this decrease was attributable principally to a reduction in PV mRNA expression per neuron rather than by a decreased density of PV mRNA-positive neurons. In contrast, the same measures of CR mRNA expression were not altered in schizophrenia. These findings were confirmed by findings from cDNA microarray studies using different probes. Across the subjects with schizophrenia, the decrease in neuronal PV mRNA expression was highly associated (r = 0.84) with the decrease in the density of neurons containing detectable levels of GAD67 mRNA. Furthermore, simultaneous detection of PV and GAD67 mRNAs revealed that in subjects with schizophrenia only 55% of PV mRNA-positive neurons had detectable levels of GAD67 mRNA. Given the critical role that PV-containing GABA neurons appear to play in regulating the cognitive functions mediated by the PFC, the selective alterations in gene expression in these neurons may contribute to the cognitive deficits characteristic of schizophrenia.

The Neurotensin Agonist PD149163 Increases Fos Expression in the Prefrontal Cortex of the Rat

“…Activation of both prefrontal cortical interneurons and pyramidal cells is consistent with the actions of atypical APDs such as clozapine (Deutch and Duman, 1996). This is particularly interesting because the number and/or function of GABA interneurons in the PFC may be compromised in schizophrenia (Hashimoto et al, 2003;Benes et al, 2000;Lewis et al, 1999;Akbarian et al, 1995). Our data suggest that NT agonists activate PFC interneurons and could thereby compensate for a prefrontal cortical GABAergic deficit in schizophrenia.…”

The translationally relevant mouse model of the 15q13.3 microdeletion syndrome reveals deficits in neuronal spike firing matching clinical neurophysiological biomarkers seen in schizophrenia

“…This is interesting, because growing evidence points to a deficient function of fast‐spiking GABAergic interneurones (Hashimoto et al . 2003, Gonzalez‐Burgos et al . 2010, Taylor & Tso 2014) as well as reduced capacity to generate gamma oscillations, as an important pathophysiological mechanism in schizophrenia (Uhlhaas & Singer 2010, Lewis et al .…”

GABAergic Neurons Immunoreactive for Calcium Binding Proteins are Reduced in the Prefrontal Cortex in Major Depression

“…Our recent unpublished observations also reveal a reduction in the density of CB-IR interneurons in dlPFC of subjects with schizophrenia (Rajkowska et al, 2002). Moreover, reductions in immunoreactivity for glutamic acid decarboxylase (GAD65) (the GABA synthesizing enzyme; Benes et al, 2000), mRNA for GAD (Akbarian et al, 1995;Hashimoto and Lewis, 2006;Hashimoto et al, 2003;Volk et al, 2000), and the GABA membrane transporter, GAT-1 (Pierri et al, 1999;Woo et al, 1998) have been observed in dlPFC and anterior cingulate cortex in manic-depressive disorder and schizophrenia. Whether similar reductions in GAD or GAT-1 mRNA and protein are present in our cohort of depressed subjects is yet to be determined.…”