Astrocytic dopamine D1 receptor modulates glutamatergic transmission and synaptic plasticity in the prefrontal cortex through d-serine.
10.1016/j.apsb.2025.07.034
- Author:
Yanan YIN
1
;
Jian HU
1
;
Haipeng WU
1
;
Xinyu YANG
1
;
Jingwen QI
1
;
Lang HUANG
1
;
Zhengyi LUO
1
;
Shiyang JIN
1
;
Nengyuan HU
1
;
Zhoucai LUO
1
;
Tong LUO
1
;
Hao CHEN
1
;
Xiaowen LI
1
;
Chunhua YUAN
1
;
Shuji LI
1
;
Jianming YANG
1
;
Yihua CHEN
1
;
Tianming GAO
1
Author Information
1. State Key Laboratory of Multi-Organ Injury Prevention and Treatment, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders, Guangdong Provincial Key Laboratory of Psychiatric Disorders, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
- Publication Type:Journal Article
- Keywords:
Astrocyte;
Dopamine D1 receptor;
Mental disorders;
Synaptic plasticity;
Synaptic transmission;
d-Serine;
mPFC
- From:
Acta Pharmaceutica Sinica B
2025;15(9):4692-4710
- CountryChina
- Language:English
-
Abstract:
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.
