Cortical Gene Expression After a Conditional Knockout of 67 kDa Glutamic Acid Decarboxylase in Parvalbumin Neurons

Abstract

In the cortex of subjects with schizophrenia, expression of glutamic acid decarboxylase 67 (GAD67), the enzyme primarily responsible for cortical GABA synthesis, is reduced in the subset of GABA neurons that express parvalbumin (PV). This GAD67 deficit is accompanied by lower cortical levels of other GABA-associated transcripts, including GABA transporter-1, PV, brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B, somatostatin, GABAA receptor α1 subunit, and KCNS3 potassium channel subunit mRNAs. In contrast, messenger RNA (mRNA) levels for glutamic acid decarboxylase 65 (GAD65), another enzyme for GABA synthesis, are not altered. We tested the hypothesis that this pattern of GABA-associated transcript levels is secondary to the GAD67 deficit in PV neurons by analyzing cortical levels of these GABA-associated mRNAs in mice with a PV neuron-specific GAD67 knockout. Using in situ hybridization, we found that none of the examined GABA-associated transcripts had lower cortical expression in the knockout mice. In contrast, PV, BDNF, KCNS3, and GAD65 mRNA levels were higher in the homozygous mice. In addition, our behavioral test battery failed to detect a change in sensorimotor gating or working memory, although the homozygous mice exhibited increased spontaneous activities. These findings suggest that reduced GAD67 expression in PV neurons is not an upstream cause of the lower levels of GABA-associated transcripts, or of the characteristic behaviors, in schizophrenia. In PV neuron-specific GAD67 knockout mice, increased levels of PV, BDNF, and KCNS3 mRNAs might be the consequence of increased neuronal activity secondary to lower GABA synthesis, whereas increased GAD65 mRNA might represent a compensatory response to increase GABA synthesis.

Structural alterations in fast-spiking GABAergic interneurons in a model of posttraumatic neocortical epileptogenesis

“…Finally, the reduction in GAD67 in UC cortex (Fig. 6) may also be related to some of the anatomical abnormalities, as decreases in this enzyme in developing neocortex result in defects in perisomatic GABAergic innervation of Pyr cells, including reductions in bouton density and size, similar to those described here (Chattopadhyaya et al, 2007); but see (Georgiev et al, 2016). …”

Pathological Basis for Deficient Excitatory Drive to Cortical Parvalbumin Interneurons in Schizophrenia

“…Experimental reductions of GAD67 in PV interneurons decrease inhibitory synaptic transmission in pyramidal cells and alter cortical network activity(48-50). Strong inhibition of pyramidal cells by PV interneurons is required for the generation of gamma oscillations in the DLPFC associated with working memory.…”

The Fragile Brain: Stress Vulnerability, Negative Affect and GABAergic Neurocircuits in Psychosis

“…132 With a different GAD1 knock-down mouse model, another group reported increased anxiety-related behavior in the open field test and light/dark box, as well as reduced effort-based behaviors, but intact spatial working memory and normal sensorimotor gating. 133 Overall, the behavioral phenotypes are not entirely consistent, 134,135 which may reflect different populations of GAD1-containing neurons besides PV+ interneurons, eg, cholecystokinin or somatostatin. While rodent models cannot be expected to capture all aspects of schizophrenia, it is notable that when PV+ neurons are targeted in a way that parallels the postmortem findings in the psychosis spectrum, an affective phenotype emerges.…”