Role of glutamic acid decarboxylase 67 in regulating cortical parvalbumin and GABA membrane transporter 1 expression: Implications for schizophrenia

Abstract

Markers of GABA neurotransmission are altered in multiple regions of the neocortex in individuals with schizophrenia. Lower levels of glutamic acid decarboxylase 67 (GAD67) mRNA and protein, which is responsible for most cortical GABA synthesis, are accompanied by lower levels of GABA membrane transporter 1 (GAT1) mRNA. These alterations are thought to be most prominent in the parvalbumin (PV)-containing subclass of interneurons, which also contain lower levels of PV mRNA. Since GAT1 and PV each reduce the availability of GABA at postsynaptic receptors, lower levels of GAT1 and PV mRNAs have been hypothesized to represent compensatory responses to an upstream reduction in cortical GABA synthesis in schizophrenia. However, such cause-and-effect hypotheses cannot be directly tested in a human illness. Consequently, we used two mouse models with reduced GAD67 expression specifically in PV neurons (PVGAD67+/−) or in all interneurons (GABAGAD67+/−) and quantified GAD67, GAT1 and PV mRNA levels using methods identical to those employed in studies of schizophrenia. Cortical levels of PV or GAT1 mRNAs were not altered in PVGAD67+/− mice during postnatal development or in adulthood. Furthermore, cellular analyses confirmed the predicted reduction in GAD67 mRNA, but failed to show a deficit in PV mRNA in these animals. Levels of PV and GAT1 mRNAs were also unaltered in GABAGAD67+/− mice. Thus, mouse lines with cortical reductions in GAD67 mRNA that match or exceed those present in schizophrenia, and that differ in the developmental timing and cell typespecificity of the GAD67 deficit, failed to provide proof-of-concept evidence that lower PV and GAT1 expression in schizophrenia are a consequence of lower GAD67 expression. Together, these findings suggest that the correlated decrements in cortical GAD67, PV and GAT1 mRNAs in schizophrenia may be a common consequence of some other upstream factor.

Early- and Late-Born Parvalbumin Basket Cell Subpopulations Exhibiting Distinct Regulation and Roles in Learning

“…reduced PV and GAD-67 levels in early-born Basket cells, accounting for greatly reduced gamma band activity and impaired prefrontal working memory support, as found in schizophrenia (Curley et al, 2013).…”

“…These results reveal how contrasting acquisition/exploitation requirements during learning are implemented through subpopulations of PV-expressing Basket cells, whose plasticity is regulated by distinct forms of learning specifically through excitation or inhibition. Because of their specific regulation properties, the two subpopulations of PV Basket cells might contribute to different mental health dysfunctions in conditions primarily affecting excitatory or inhibitory neurotransmission such as schizophrenia or autism (Chao et al, 2010;Curley et al, 2013;Han et al, 2014).…”

Regulation of Parvalbumin Basket cell plasticity in rule learning

“…Deficits in the strength of inhibitory transmission might impair late-born PV neuron plasticity in mental retardation and autism [33e35], whereas deficits in the strength of excitatory transmission might account for greatly reduced gamma band activity and impaired prefrontal working memory support as found in schizophrenia [36].…”

Effects of γ-aminobutyric acid on the thymus tissue structure, antioxidant activity, cell apoptosis, and cytokine levels in chicks under heat stress

“…In the present study, we found that the chicks treated with GABA showed elevated activity of SOD and GSH-Px in thymus. This could be attributed to the large amount of glutamic acid produced from metabolism of GABA (Curley et al 2013). Glutamic acid is the key element for synthesis of GSH-Px, which maintains the GSH-Px level in vivo, and therefore improves the activity of antioxidant enzymes.…”