Thalamofrontal synaptic weakening underlies short-term memory deficits from adolescent NMDAR hypofunction

초록

N-methyl-D-aspartate receptor (NMDAR) hypofunction is implicated in the pathophysiology of schizophrenia and other psychiatric disorders. A prevailing model attributes its effects to impaired inhibitory interneurons, leading to excitation–inhibition (E–I) imbalance and cortical hyperexcitability. However, this framework does not explain the circuit-specific cognitive deficits observed in patients. Here, we show that chronic adolescent NMDAR hypofunction produces short-term memory (STM) impairments through selective weakening of thalamofrontal (TF) synaptic transmission, rather than global E–I imbalance. In a mouse model of repeated ketamine exposure, STM deficits were accompanied by reduced release probability and vesicle refilling at mediodorsal thalamus (MD) → dorsomedial prefrontal cortex (dmPFC) synapses,without changes in local cortical connectivity, intrinsic excitability, or synaptic ultrastructure. These presynaptic changes were associated with diminished turn direction– dependent activity in the dmPFC and impaired Y-maze performance. Strikingly, chemogenetic activation of MD→dmPFC projections restored both directional selectivity and behavioral performance. Our findings reveal a circuit-specific presynaptic mechanism linking adolescent NMDAR hypofunction to cognitive deficits, challenging interneuron-centric models and highlighting TF synapses as a potential therapeutic target in disorders with NMDAR dysregulation.