Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia

Abstract

In subjects with schizophrenia, impairments in working memory are associated with dysfunction of the dorsolateral prefrontal cortex (DLPFC). This dysfunction appears to be due, at least in part, to abnormalities in c-aminobutyric acid (GABA)-mediated inhibitory circuitry. To test the hypothesis that altered GABA-mediated circuitry in the DLPFC of subjects with schizophrenia reflects expression changes of genes that encode selective presynaptic and postsynaptic components of GABA neurotransmission, we conducted a systematic expression analysis of GABA-related transcripts in the DLPFC of 14 pairs of schizophrenia and age-, sex-and post-mortem interval-matched control subjects using a customized DNA microarray with enhanced sensitivity and specificity. Subjects with schizophrenia exhibited expression deficits in GABA-related transcripts encoding (1) presynaptic regulators of GABA neurotransmission (67 kDa isoform of glutamic acid decarboxylase (GAD 67 ) and GABA transporter 1), (2) neuropeptides (somatostatin (SST), neuropeptide Y (NPY) and cholecystokinin (CCK)) and (3) GABA A receptor subunits (a1, a4, b3, c2 and d). Real-time qPCR and/or in situ hybridization confirmed the deficits for six representative transcripts tested in the same pairs and in an extended cohort, respectively. In contrast, GAD 67 , SST and a1 subunit mRNA levels, as assessed by in situ hybridization, were not altered in the DLPFC of monkeys chronically exposed to antipsychotic medications. These findings suggest that schizophrenia is associated with alterations in inhibitory inputs from SST/NPY-containing and CCKcontaining subpopulations of GABA neurons and in the signaling via certain GABA A receptors that mediate synaptic (phasic) or extrasynaptic (tonic) inhibition. In concert with previous findings, these data suggest that working memory dysfunction in schizophrenia is mediated by altered GABA neurotransmission in certain DLPFC microcircuits.

Specificity and timing of neocortical transcriptome changes in response to BDNF gene ablation during embryogenesis or adulthood

“…4,[75][76][77][78][84][85][86][87][88] Importantly, just as in our current study of BDNF- ablated animals, SST, NPY and RGS4 transcripts are downregulated in the prefrontal cortex (PFC) of subjects with schizophrenia. 29,89,90 However, we acknowledge that other, BDNF-independent mechanisms may also account for the altered expression of these genes in schizophrenia. 91,92 The extent to which a BDNF-dependent transcriptome profile is present in schizophrenia remains to be established in hypothesis-driven assessment of gene expression changes in the human PFC.…”

Neuroplasticity in Depressed Individuals Compared with Healthy Controls

“…Although robust changes in cortical GAD67 mRNA are not typically found in the PFC of individuals with depression (Thompson et al, 2009;Sibille et al, 2011), significant decreases in somatostatin suggest that interneuron deficits may be especially prominent in a subset of interneurons shown to directly contribute to cortical plasticity (Lazarus and Huang, 2011). As inhibitory interneuron deficits are shared among those with depression, bipolar disorder, and schizophrenia (Thompson et al, 2009(Thompson et al, , 2011Fung et al, 2010;Hashimoto et al, 2008;Daskalakis et al, 2002), cortical plasticity deficits would also be expected to be found in multiple forms of psychopathology.…”

Activation of GABAA receptors in the medial prefrontal cortex produces an anxiolytic-like response

“…The GABAergic connection between PFC and other brain structures is probably also involved in modulation of anxiety-related behaviours (28,29). Previous studies have reported that GABA-containing neurons in the rat ventral tegmental area project to the PFC and GABAergic projections from PFC also innervate different brain regions such as the nucleus accumbens (11,30).…”