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bioRxiv · 10.1101/2025.11.11.687794

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

Yu, J.·Choi, I. S.·Kim, G. H.·Bahn, S.·Bae, S.·Lee, T.·Choi, J. H.·Kwon, J. S.·Kim, M.·Lee, K. J.·Rah, J.-C.
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Abstract

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) [->] dorsomedial prefrontal cortex (dmPFC) synapses, without detectable changes in layer 2/3 [->] 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 [->] 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.

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Yu, J., Choi, I. S., Kim, G. H., Bahn, S., Bae, S., Lee, T., Choi, J. H., Kwon, J. S., Kim, M., Lee, K. J., Rah, J.-C.. 2025-11-12. Thalamofrontal synaptic weakening underlies short-term memory deficits from adolescent NMDAR hypofunction. https://doi.org/10.1101/2025.11.11.687794

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