Phencyclidine and methamphetamine cause cognitive deficits by changing pyramidal neuron transmitter identity in the prefrontal cortex

Abstract

ABSTRACTDecreased cognitive ability is a major consequence of exposure to drugs of abuse, but the underlying neuroplastic changes have been elusive. We show that both phencyclidine and methamphetamine cause a population of prelimbic pyramidal neurons to switch from a glutamatergic to a GABAergic phenotype. Overriding the gain of GABA with RNA-interference prevents drug-induced cognitive deficits and locomotor sensitization, connecting the change in neurotransmitter identity with altered behavior. Chemogenetic suppression of drug-induced hyperactivity also prevents the change in transmitter phenotype or reverses it after it has occurred, preventing or rescuing the associated behavioral changes. These findings may provide therapeutic opportunities to mitigate drug-induced cognitive deficits by manipulating electrical activity in the prelimbic cortex.