["The Journal of Physiology, EarlyView. ", "\nAbstract figure legend Adolescent mice [postnatal days (P)45–51] received a systemic injection of ketamine (30 mg/kg). The long‐term effects were then evaluated in adulthood (P60–P90) using whole‐cell patch‐clamp electrophysiology. Recordings were obtained from layer 2/3 pyramidal neurons (PyNs) and parvalbumin‐positive interneurons (PV‐INs) in the prelimbic medial prefrontal cortex (mPFC) of wild‐type and PV‐Cre × Ai9 mice. Synaptic measures included glutamatergic and GABAergic transmission and spike‐timing‐dependent plasticity (STDP) in pyramidal neurons, as well as the intrinsic firing properties of PV‐INs. Exposure to ketamine during adolescence decreased inhibitory synaptic transmission and impaired the excitability of PV‐INs. This led to a sustained shift in the prefrontal excitation–inhibition balance and long‐lasting changes in synaptic plasticity that persisted into adulthood.\n\n\n\n\n\n\n\n\n\nAbstract\nThe medial prefrontal cortex (mPFC) undergoes extensive GABAergic interneuron maturation during adolescence, a process that establishes excitatory–inhibitory balance and supports adult cognitive function. Disruptions during this critical developmental period contribute to neuropsychiatric disorders, yet the enduring consequences for adult synaptic plasticity remain poorly understood. Here we examine how adolescent NMDA receptor (NMDAR) hypofunction impacts adult mPFC transmission and plasticity. We exposed adolescent mice to subanaesthetic ketamine and performed whole‐cell patch‐clamp recordings in adulthood to examine excitatory and inhibitory synaptic currents and spike timing‐dependent plasticity (STDP). Ketamine‐exposed mice exhibited persistent GABAergic transmission deficits in pyramidal neurons (PyNs), as evidenced by reduced spontaneous and miniature IPSC frequencies and elevated paired‐pulse ratios, consistent with impaired presynaptic GABA release and reduced functional output of parvalbumin‐positive interneurons (PV‐INs). PyN STDP was altered in ketamine‐exposed mice, with spike pairings in the post‐before‐pre order inducing potentiation, in contrast to the synaptic depression observed in vehicle mice. Together, these results demonstrate that adolescent NMDAR hypofunction produces enduring impairments in PV‐IN‐mediated inhibitory transmission and disrupts the bidirectional expression of STDP in the adult mPFC. This shift in plasticity rules reflects a loss of inhibitory control over synaptic integration and indicates that developmental NMDAR disruption produces persistent alterations in cortical circuit function. Together, these findings provide mechanistic insight into how adolescent NMDAR hypofunction leads to enduring circuit dysfunction, with relevance to neurodevelopmental disorders emerging during adolescence.\n\n\n\n\n\n\n\n\n\nKey points\n\nAdolescence is a critical period for GABAergic maturation in the medial prefrontal cortex (mPFC).\nAdolescent ketamine exposure reverses adult mPFC spike timing‐dependent plasticity from depression to potentiation.\nAdolescent ketamine exposure impairs GABAergic transmission in adulthood.\nAdolescent ketamine exposure reduces the functional output of parvalbumin‐positive interneurons.\nThese findings demonstrate that adolescent NMDA receptor hypofunction disrupts adult prefrontal inhibitory balance and reverses plasticity polarity.\n\n\n"]