Chronic ketamine administration during adolescence in mice produces long-lasting changes in synaptic integration in the dorsal hippocampal dentate gyrus, specifically expanding the temporal window for inputs from the inner molecular layer but not the medial perforant path. Ketamine also reduces inhibitory synaptic efficacy, likely by decreasing the number and function of parvalbumin-positive interneurons, thereby altering the excitatory/inhibitory balance. These findings suggest that adolescent ketamine exposure strongly affects inhibitory synaptic function mediated by parvalbumin neurons, ultimately impacting synaptic integration in adulthood and may help explain the heightened vulnerability of the adolescent brain.
Adolescent mice given ketamine, which blocks NMDA receptors, showed lasting deficits in GABAergic inhibition in the medial prefrontal cortex as adults. Recordings from pyramidal neurons revealed reduced spontaneous and miniature inhibitory currents and altered paired-pulse ratios, indicating impaired presynaptic GABA release and diminished function of parvalbumin-positive interneurons. Spike-timing-dependent plasticity was also disrupted: spike pairings that normally cause depression instead induced potentiation. These results suggest that NMDA receptor hypofunction during adolescence produces enduring impairments in inhibitory transmission and shifts plasticity rules, providing mechanistic insight into circuit dysfunction relevant to neurodevelopmental disorders.