@article{APS11426,
author = {Yuan-ping Dong and Yun Wu and Yi-lu Zhao and Yu-min Chen and Tong-ye Liu and Yi-he Zhang and Jie-ying Xie and Jin-feng Zhang and Han Zhang and He Chen and Yu Peng and Chun-lei Zhang and Andrew R. Rau and Kasper B. Hansen and Hai-bing Xu and Feng Yi},
title = {GluN2A-NMDA receptor inhibition disinhibits the prefrontal cortex, reduces forced swim immobility, and impairs sensorimotor gating},
journal = {Acta Pharmacologica Sinica},
volume = {47},
number = {1},
year = {2025},
keywords = {},
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.},
issn = {1745-7254}, url = {http://www.chinaphar.com/article/view/11426}
}