The 5-Hydroxytryptamine 2C Receptor Agonist Improves Sensorimotor Gating and Cognitive Deficits by Reversing Excitation/Inhibition Imbalance in the Medial Prefrontal Cortex

BACKGROUND AND HYPOTHESIS: Although the 5-hydroxytr-yptamine 2C receptor (5-HT2C) receptor agonists have demonstrated efficacy in mitigating sensorimotor gating deficits in the schizophrenic animal model of glutamatergic dysfunction, the precise neural mechanisms underlying these effects remain incompletely understood. This study investigates how 5-HT2C receptor activation improves sensorimotor gating and cognitive function by modulating Excitation/Inhibition balance in the medial prefrontal cortex (mPFC). STUDY DESIGN: We first employed chemogenetic approach-es to establish that selective activation of Htr2c-express-ing neurons in the mPFC rescues sensorimotor gating and cognitive deficits. Subsequent electrophysiological recordings were used to examine whether a 5-HT2C receptor agonist normalizes the MK-801 induced Excitation/Inhibition imbalance via facilitation of GABAergic neuron activity in the mPFC. Finally, we verified that the beneficial effects of the 5-HT2C agonist on sensorimotor gating and cognition depend specifically on the activation of mPFC GABAergic neurons. STUDY RESULTS: 5-HT2C receptor knockout mice exhibited intact sensorimotor gating (ie, prepulse inhibition, PPI), working memory (assessed by temporal order memory), long-term memory, and locomotor activity. Chemogenetic activation of mPFC Htr2c-expressing neurons reversed MK-801 induced impairments in PPI, working memory, and long-term memory, without affecting hyperlocomotion. The 5-HT2C receptor agonist enhanced firing of mPFC GABAergic neurons, normalized the MK-801 elevated Excitation/Inhibition ratio. Importantly, chemogenetic inhibition of mPFC GABAergic neurons abolished the therapeutic effects of the 5-HT2C agonist. CONCLUSIONS: These findings indicate that 5-HT2C receptor activation in the mPFC ameliorates sensorimotor gating and cognitive deficits by enhancing GABAergic neurotransmission, thereby re-establishing cortical Excitation/Inhibition balance.