GAD67 Deficiency in Parvalbumin Interneurons Produces Deficits in Inhibitory Transmission and Network Disinhibition in Mouse Prefrontal Cortex

Abstract

In mammalian neocortex, the delicate balance of neural circuits is regulated by a rich repertoire of inhibitory control mechanisms mediated by diverse classes of GABAergic interneurons. A key step common to all GABAergic neurons is the synthesis of GABA, catalyzed by 2 isoforms of glutamic acid decarboxylases (GAD). Among these, GAD67 is the rate-limiting enzyme. GAD67 level is regulated by neural activity and is altered in multiple neuropsychiatric disorders. The significance of altered GAD67 levels on inhibitory transmission, however, remains unclear. The presence of GAD65, postsynaptic GABA receptor regulation, and the diversity of cortical interneurons make the link from GAD67 levels to GABA transmission less than straightforward. Here, we selectively removed one allele of the GAD67 gene, Gad1, in PV interneurons in juvenile mice. We found substantial deficits in transmission from PV to pyramidal neurons in prefrontal cortex, along with increases of pyramidal cell excitability and excitation/inhibition balance in PV cells. Synaptic deficits recovered in adult mice, suggesting engagement of homeostatic and compensatory mechanisms. These results demonstrate that GAD67 levels directly influence synaptic inhibition. Thus, GAD67 deficiency in PV cells likely contributes to cortical dysfunction in disease states; the reversibility of synaptic deficits suggests nonpermanent damage to inhibitory circuitry.

Glutamate Decarboxylase 67 Deficiency in a Subset of GABAergic Neurons Induces Schizophrenia-Related Phenotypes

“…Haploinsufficiency of the GAD67 gene in a subset of GABAergic neurons, primarily in PV neurons, gives rise to schizophrenia-related endophenotypes and alterations in both excitatory and inhibitory synaptic functions. These findings are consistent, in several respects, with results of other reports (Brown et al, 2015;Lazarus et al, 2013). Therefore, our findings support the hypothesis that GAD67 deficiency is a possible common pathway that induces the pathogenesis of schizophrenia and provide a novel link between GAD67 deficiency and impaired NMDA-mediated synaptic transmission.…”

MeCP2 regulates the timing of critical period plasticity that shapes functional connectivity in primary visual cortex

“…It is now well established, largely from studies in rodent primary visual cortex, that the maturation of GABAergic inhibition mediated by a fast-spiking PV interneuron network is a crucial mechanism for triggering the onset and regulating the progression of the critical period for functional wiring in V1 (16,46). Upon eye opening at ∼P13, visual experience stimulates substantial and progressive activity-dependent maturation of PV cell morphology, connectivity, and physiological properties (18,24,43,47). Visual acuity of MeCP2 −/y mice is comparable to that of WT mice at the time of eye opening, as measured by an optomotor task (21).…”

“…However, 2-3 d after vision onset (by P15), we found substantial molecular changes (e.g., in GAD67, GAD65, vGAT, PV, and PNN), especially in PV cells, which are indicative of physiological changes. As a rate-limiting GABA synthetic enzyme, GAD67 expression is highly sensitive to input and network activity and directly impacts the magnitude GABAergic transmission (43,48). Because GAD67 is expressed in all cortical GABAergic neurons and yet appears to manifest cell-typespecific regulation (49), it is crucial to examine activity regulation of GAD67 transcription with laminar and cell-type resolution.…”

“…Among the several molecular alterations in V1 of MeCP2 −/y mice, GAD67 likely has the most significant effect on cellular/ vesicular GABA contents and directly impacts the strength of GABA transmission (43). To determine whether the precocious rise in GAD67 expression after eye opening in MeCP2 −/y mice is a key event in triggering an earlier onset of the critical period, we reduced GAD67 expression by crossing a germ-line gad1 +/− heterozygous allele into the MeCP2 −/y background.…”

Neurodevelopment, GABA System Dysfunction, and Schizophrenia

“…PV þ interneurons are selectively disrupted by exogenous GABA potentiation (Haas et al, 2013;Levav-Rabkin et al, 2010). During adolescence, when cells have finished migrating and cortical circuits are maturing, GAD1 suppression decreases axonal branching in PV þ cells in a cell autonomous manner (Chattopadhyaya et al, 2007) and increases pyramidal cell activity (Lazarus et al, 2013). Adult mice with GAD1 gene expression deficits in restricted interneuron populations have distinct molecular and behavioral dysfunction depending on the affected cell type Kvitsiani et al, 2013;Schmidt et al, 2013).…”