Adolescent administration of ketamine impairs excitatory synapse formation onto parvalbumin-positive GABAergic interneurons in mouse prefrontal cortex.

Adolescent ketamine abuse causes lasting deficits in cognition and social behavior by reducing excitatory synapses on parvalbumin (PV) inhibitory neurons in the medial prefrontal cortex (mPFC), while sparing excitatory pyramidal neurons. In rats given sub-chronic ketamine during early adolescence, the density of these synapses remained lower into adulthood, leading to hyperexcitability, impaired working memory, and reduced social interaction compared to controls. Bioinformatic analysis revealed decreased expression of a gene co-expression module (M1) critical for inhibitory neuron synapse development. The findings suggest that adolescent ketamine exposure irreversibly disrupts synaptic development, pointing to potential therapeutic targets.

Study at a glance

Abstract

Ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, induces deficits in cognition and information processing following chronic abuse. Adolescent ketamine misuse represents a significant global public health issue; however, the neurodevelopmental mechanisms underlying this phenomenon remain largely elusive. This study investigated the long-term effects of sub-chronic ketamine (Ket) administration on the medial prefrontal cortex (mPFC) and associated behaviors. In this study, Ket administration during early adolescence displayed a reduced density of excitatory synapses on parvalbumin (PV) neurons persisting into adulthood. However, the synaptic development of excitatory pyramidal neurons was not affected by ketamine administration. Furthermore, the adult Ket group exhibited hyperexcitability and impaired socialization and working memory compared to the saline (Sal) administration group. These results strongly suggest that sub-chronic ketamine administration during adolescence results in functional deficits that persist into adulthood. Bioinformatic analysis indicated that the gene co-expression module1 (M1) decreased expression after ketamine exposure, which is crucial for synapse development in inhibitory neurons during adolescence. Collectively, these findings demonstrate that sub-chronic ketamine administration irreversibly impairs synaptic development, offering insights into potential new therapeutic strategies.