Authors
Jinseon Yu, In Sun Choi, Gyu Hyun Kim, Sangkyu Bahn, Jinmo Kim, Sungwon Bae, Taekwan Lee, Joon Ho Choi, Jun Soo Kwon, Minah Kim, Ji-Woong Choi, Kea Joo Lee, Jong-Cheol Rah
Published in
Science advances. Volume 12. Issue 39. Pages eaee2152. Sep 25, 2026. Epub Sep 23, 2026.
Abstract
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.
PMID:
42777060
Bibliographic data and abstract were imported from PubMed on 24 Sep 2026.
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