Chemogenetic Restoration of the "Excitation-Inhibition" Imbalance in the Medial Prefrontal Cortex Ameliorates Schizophrenia-Like Sensory Gating Deficits.

Abstract

AIM: Sensory gating is a neurological mechanism that filters out irrelevant sensory input, protecting cognitive processing from sensory overload. Patients with schizophrenia usually lack sensory gating, which severely affects normal cognitive functions due to an overload of irrelevant information. Sensory gating and cognitive tasks have been found to need moderate activity in the medial prefrontal cortex (mPFC). However, the specific control mechanisms of the mPFC remain unknown. We assume that the "Excitation-Inhibition" imbalance in the mPFC can induce schizophrenia-like sensory gating and cognitive defects. METHODS: The current study utilized chemogenetics and FloxP-Cre techniques to examine the distinct roles of glutamatergic and GABAergic neurons in the mPFC in regulating sensory gating and cognitive functions, both in healthy and schizophrenia-like mouse models. RESULTS: Manipulation of neural activity in the mPFC, specifically inhibiting GABAergic neurons or stimulating glutamatergic neurons in the mPFC, caused schizophrenia-like sensory gating deficits, disturbances in temporal order and long-term recognition memory, and hyperlocomotion. Conversely, activating GABAergic neurons or inhibiting glutamatergic neurons mitigated these schizophrenia-like symptoms, including sensory gating deficits, temporal order memory impairments, and hyperlocomotion. CONCLUSIONS: We discovered that a disturbance in the "Excitation-Inhibition" balance in the mPFC significantly contributes to schizophrenia-like sensory gating deficits, cognitive impairments, and hyperlocomotion. Remarkably, correcting this imbalance in schizophrenia-like mice alleviated these deficits, providing profound insights into the regulatory functions of glutamatergic and GABAergic neurons in the mPFC.