Genetic and pharmacological manipulations of parvalbumin interneurons: Relevance to neuropsychiatric disease.

摘要

Much work has shown that Parvalbumin+ (PV) interneurons, in particular the Fast Spiking Basket Cell, are major regulators of gamma-band activity in the cortex and hippocampus. Gamma rhythms, which are linked to attention, learning, and cognition, are depressed or altered in several key neurologic and psychiatric conditions, including schizophrenia and autism. Considerable evidence has demonstrated PV interneurons to be rigid regulators of neuronal activity, similar to a clock or a timer; however, in the past several years, evidence points to the ability of these cells to exert considerable modulatory influence on networks. For example, PV interneurons are surrounded by rings of dense extracellular matrix, termed perineuronal nets (PNN), which regulate plasticity in the visual cortex during development, as well as long-term potentiation and memory in the limbic lobe. Additionally, PV interneurons express extrasynaptic delta-subunit containing GABAA receptors (delta-GABAARs) that mediate tonic inhibition. In addition to regulating the excitability of these cells, delta-GABAARs are sensitive to levels of metabolites of progesterone and adrenal corticoids (i.e., neurosteroids), which are potent allosteric modulators of these receptors. Here, through a pharmacological and genetic model, we investigated the role of PV interneuron-expressed delta-GABAARs in behavior and neural rhythms. We show that ketamine, a non-competitive NMDA receptor antagonist shown to damage hippocampal PV interneurons, reduces and alters the PNNs surrounding these cells, as well as the expression of PV, and produces a behavioral phenotype consistent with schizophrenia. We next investigated the effect of conditionally knocking out the delta-GABAA receptor from PV interneurons. This resulted in altered gamma frequency and sensorimotor gating. Collectively, these results indicate that PV interneurons are capable of modulating cognition and behavior through tonic inhibitory currents. While other studies have demonstrated a role of tonic inhibition in behavior before, this is the first study to demonstrate interneuron-specific consequences of reduced delta-GABAAR expression.