Astrocytic dopamine D1 receptor modulates glutamatergic transmission and synaptic plasticity in the prefrontal cortex through D-serine

Available online 26 July 2025

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The prefrontal cortex (PFC) plays a pivotal role in orchestrating higher-order emotional and cognitive processes, a function that depends on the precise modulation of synaptic activity. Although pharmacological studies have demonstrated that dopamine signaling through dopamine D1 receptor (DRD1) in the PFC is essential for these functions, the cell-type-specific and molecular mechanisms underlying the neuromodulatory effects remain elusive. Using cell-type-specific knockout mice and patch-clamp recordings, we investigated the regulatory role of DRD1 on neurons and astrocytes in synaptic transmission and plasticity. Furthermore, we explored the mechanisms by which DRD1 on astrocytes regulate synaptic transmission and plasticity at the cellular level, as well as emotional and cognitive functions at the behavioral level, through two-photon imaging, microdialysis, high-performance liquid chromatography, transcriptome sequencing, and behavioral testing. We found that conditional knockout of the Drd1 in astrocytes (CKOAST) increased glutamatergic synaptic transmission and long-term potentiation (LTP) in the medial prefrontal cortex (mPFC), whereas Drd1 deletion in pyramidal neurons did not affect synaptic transmission. The elevated level of D-serine in the mPFC of CKOAST mice increased glutamatergic transmission and LTP through NMDA receptors. In addition, CKOAST mice exhibited abnormal emotional and cognitive function. Notably, these behavioral changes in CKOAST mice could be reversed through the administration of D-serine degrease to the mPFC. These results highlight the critical role of the astrocytic DRD1 in modulating mPFC synaptic transmission and plasticity, as well as higher brain functions through D-serine, and may shed light on the treatment of mental disorders.

Graphical abstractThe dopamine D1 receptor (DRD1) in astrocytes modulates synaptic transmission and plasticity in the medial prefrontal cortex (mPFC), thereby influencing emotional and cognitive behaviors, via the action of D-serine.