2. Academic Validation
  3. GluN2A-NMDA receptor inhibition disinhibits the prefrontal cortex, reduces forced swim immobility, and impairs sensorimotor gating

GluN2A-NMDA receptor inhibition disinhibits the prefrontal cortex, reduces forced swim immobility, and impairs sensorimotor gating

  • Acta Pharmacol Sin. 2025 Sep 10. doi: 10.1038/s41401-025-01643-2.
Yuan-Ping Dong # 1,  Yun Wu # 1,  Yi-Lu Zhao # 1,  Yu-Min Chen 1,  Tong-Ye Liu 1,  Yi-He Zhang 1,  Jie-Ying Xie 1,  Jin-Feng Zhang 1,  Han Zhang 1,  He Chen 1,  Yu Peng 2,  Chun-Lei Zhang 3,  Andrew R Rau 4,  Kasper B Hansen 4,  Hai-Bing Xu 5,  Feng Yi 6
Affiliations

Affiliations

  • 1 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 Province 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.
  • 2 Department of Neurology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510006, China.
  • 3 Institut Pasteur, Université de Paris, Neural Circuits for Spatial Navigation and Memory, F-75015, Paris, France.
  • 4 Center for Structural and Functional Neuroscience, Center for Biomolecular Structure and Dynamics, Division of Biological Sciences, University of Montana, Missoula, MT, USA.
  • 5 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 Province 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. haibingxu@smu.edu.cn.
  • 6 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 Province 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. fengyi2020@smu.eud.cn.
  • # Contributed equally.
PMID: 40931040 DOI: 10.1038/s41401-025-01643-2
Abstract

Recent investigations into the rapid antidepressant effects of ketamine, along with studies on schizophrenia-related susceptibility genes, have highlighted the GluN2A subunit as a critical regulator of both emotion and cognition. However, the specific impacts of acute pharmacological inhibition of GluN2A-containing NMDA receptors on brain microcircuits and the subsequent behavioral consequences remain poorly understood. In this study, we first examined the effects of MPX-004, a selective GluN2A NMDA Receptor Inhibitor, on behavior within the dorsomedial prefrontal cortex (dmPFC). Local administration of MPX-004 in the dmPFC led to a reduced immobility duration in the forced swim test, an acute antidepressant-like effect, impairments in sensorimotor gating, and a schizophrenia-like phenotype. In vivo multiple-channel recordings and c-Fos staining revealed that MPX-004 decreases the activity of parvalbumin-expressing interneurons (PV-INs) and increases the activity of pyramidal neurons (PYNs). In vivo patch-clamp recordings further confirmed that PV-IN inactivation leads to an elevated PYN firing rate in the PFC. In vitro whole-cell recordings demonstrated that PV-INs receive stronger excitatory synaptic input and respond more robustly to presynaptic stimulation than do somatostatin-expressing interneurons (SST-INs) and PYNs, rendering them susceptible to GluN2A inhibition. Finally, the specific knockdown of GluN2A in prefrontal PV-INs abolished the behavioral effects of MPX-004, underscoring a critical role of the GluN2A-mediated modulation of PV-INs in these phenotypes. Together, these findings reveal that PV-INs are particularly vulnerable to GluN2A inhibition, leading to disinhibition of prefrontal circuits and resulting in both antidepressant-like and schizophrenia-like behaviors.

Keywords

NMDA receptor; disinhibition; microcircuit; prefrontal cortex; psychiatry.

Figures
Products