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

Abstract

During adolescence, the prefrontal cortex (PFC) undergoes significant developmental changes, affecting 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 is disrupted in schizophrenia (SZ). While acute NMDA receptor (NMDAr) blockade leads to excess glutamate transmission in the PFC, less is known about the long-term impacts of NMDAr blockade in adolescence on the E/I balance and adult cognitive function and social behavior. Here we show that early-adolescence chronic MK-801 administration leads to deficits in recognition memory and social function as well as increased E/I balance in the medial prefrontal cortex (mPFC) of adult male rats, stemming from reduced inhibitory synaptic transmission rather than changes in excitatory transmission or intrinsic excitability. Interestingly, chemogenetic attenuation of prelimbic mPFC pyramidal neurons reverses adolescent MK-801-induced deficits in recognition memory, but not social behavior. These findings emphasize the critical role of intact NMDAr function during adolescence on behavior in adulthood and on the E/I balance, and imply that reduced mPFC pyramidal neuron activity may hold therapeutic potential in treating recognition memory deficits in SZ.