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

AI Summary

Adolescent NMDAR antagonism with ketamine causes STM deficits by impairing mediodorsal thalamus to dorsomedial prefrontal cortex synaptic transmission.
Projection-specific presynaptic impairments: reduced release probability and attenuated short-term depression at MD to dmPFC synapses, without corticocortical or excitability changes.
Chemogenetic strengthening of MD to dmPFC projections restores direction-selective coding and delayed alternation performance, identifying TF synapses as therapeutic targets.

TL;DR (AI Generated)

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 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.

Basic summary

Sci Adv. 2026 Sep 25;12(39):eaee2152. doi: 10.1126/sciadv.aee2152. Epub 2026 Sep 23.

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 | DOI:10.1126/sciadv.aee2152

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