Inhibition of parvalbumin-expressing interneurons results in complex behavioral changes

Abstract

Reduced expression of the GAD1 gene-encoded 67-kD protein isoform of glutamic acid decarboxylase (GAD67) is a hallmark of the schizophrenia. GAD67 downregulation occurs in multiple interneuronal subpopulations, including the parvalbumin positive (PVALB+) cells. To investigate the role of the PV-positive GABA-ergic interneurons in behavioral and molecular processes, we knocked down the Gad1 transcript using a miRNA engineered to specifically target Gad1 mRNA under the control of Pvalb bacterial artificial chromosome. Verification of construct expression was performed by immunohistochemistry. Follow-up electrophysiological studies revealed a significant reduction in GABA release probability without alterations in postsynaptic membrane properties or changes in glutamatergic release probability in prefrontal cortex pyramidal neurons. Behavioral characterization of our transgenic mice uncovered that the Pvalb/Gad1 Tg mice have pronounced sensorimotor gating deficits, increased novelty seeking and reduced fear extinction. Furthermore, NMDA receptor antagonism by ketamine had an opposing dose-dependent effect, suggesting that the differential dosage of ketamine might have divergent effects on behavioral processes. All behavioral studies were validated using a second cohort of animals. Our results suggest that reduction of GABA-ergic transmission from PVALB+ interneurons primarily impacts behavioral domains related to fear and novelty seeking and that these alterations might be related to the behavioral phenotype observed in schizophrenia.

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.…”

Multimodal and Site-Specific Plasticity of Amygdala Parvalbumin Interneurons after Fear Learning

“…However, such plasticity may also be a precipitating factor for escalating fear and anxiety in PTSD. Indeed, preclinical animal models suggest that PV-IN dysfunction may be involved in pathological, extinction-resistant fear (Bissonette et al, 2014; Brown et al, 2015; Lucas et al, 2014). Therefore, experiments should examine whether chronic stress or trauma is associated with altered inhibitory plasticity and whether these effects may underlie progression to emotional dysfunction.…”

Hippocampal arterial cerebral blood volume in early psychosis

“…Future animal studies need to directly test NMDA receptor hypofunction vs interneuron dysfunction. One possible way is to generate animal models that selectively suppress a subpopulation of interneurons (Brown et al, 2015). Hippocampal CBV maps from these models before and after ketamine administration can then be compared with results from human studies to draw stronger inferences about underlying mechanisms of psychosis.…”