Chemogenetic attenuation of PFC pyramidal neurons restores deficits in recognition memory following adolescent NMDA receptor blockade

Abstract

During adolescence, the prefrontal cortex (PFC) undergoes dramatic developmental changes, including fine-tuning the balance between excitatory glutamate and inhibitory GABA transmission (i.e., the E/I balance). This process is critical for intact cognitive function and social behavior in adulthood, and its disruption is associated with several psychiatric disorders including schizophrenia (SZ). While acute NMDA receptor (NMDAr) blockade leads to excess glutamate transmission in the PFC, the long-term consequences of MK-801 administration during early adolescence on the E/I balance in adulthood have not been extensively studied. In the current study, we show that chronic MK-801 administration during early adolescence leads to abnormalities in recognition memory and social behavior as well as reduced frequency of miniature inhibitory post-synaptic currents (mIPSCs) in mPFC of adult male rats, with no change in excitatory currents or basal activity. We further show that chemogenetic attenuation of prelimbic mPFC pyramidal neurons reversed deficits in recognition memory, but not social behavior. These findings emphasize the critical role played by NMDAr during adolescence on the E/I balance as well as cognition and social function in adulthood. Moreover, these findings implicate the therapeutic outcomes of reduced mPFC pyramidal neuron activity in recognition memory deficits in early-adolescence MK-801-treated rats. Since recognition memory deficits are key components of the cognitive deficits in SZ, these findings suggest that the future development of treatments aimed at alleviating the cognitive deficits in SZ should focus on regulating the prefrontal E/I balance.