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

N-methyl-D-aspartate receptor (NMDAR) hypofunction is linked to schizophrenia, but prevailing models centered on reduced number and activity of inhibitory interneurons and the resulting excitation-inhibition (E-I) imbalance do not explain selective cognitive impairments. Here, we show that repeated adolescent NMDAR antagonism produces short-term memory (STM) deficits by weakening thalamofrontal (TF) synaptic transmission. In mice repeatedly exposed to ketamine, STM impairment coincided with reduced release probability and vesicle refilling at mediodorsal thalamus (MD) to dorsomedial prefrontal cortex (dmPFC) synapses, without detectable changes in layer 2/3 to layer 2/3 synaptic release probability, intrinsic excitability, or synaptic ultrastructure. These presynaptic deficits were accompanied by diminished direction-selective population coding in the dmPFC as revealed by decoding analysis and impaired delayed alternation performance in the Y-maze. Chemogenetic strengthening of MD to dmPFC projections restored both neural selectivity and behavior. Our findings identify a circuit-specific presynaptic mechanism linking adolescent NMDAR hypofunction to cognitive dysfunction, challenging interneuron-centric models and establishing TF synapses as a potential therapeutic target in NMDAR-related disorders.