Thalamofrontal (TF) dysconnectivity is one of the most consistent circuit-level abnormalities reported in patients with schizophrenia and is linked to deficits in short-term memory (STM). However, the biological mechanisms underlying TF weakening remain unclear. Here, we show that repeated adolescent N-methyl-d-aspartate receptor (NMDAR) antagonism produces STM deficits by impairing TF synaptic transmission. In mice repeatedly exposed to ketamine, STM impairment coincided with reduced release probability and attenuated short-term depression at mediodorsal thalamus (MD) → dorsomedial prefrontal cortex (dmPFC) synapses, without detectable changes in corticocortical synaptic release probability, intrinsic excitability, or gross synaptic ultrastructure. These presynaptic deficits were accompanied by diminished direction-selective population coding in the dmPFC and impaired delayed alternation performance. Chemogenetically strengthening MD → dmPFC projections restored both neural selectivity and behavior. These findings identify a projection-specific presynaptic mechanism through which adolescent NMDAR hypofunction weakens TF communication and produces cognitive impairment, offering a biological explanation for clinically observed TF dysconnectivity and establishing TF synapses as a therapeutic target.