Dong Yuan-Ping, Wu Yun, Zhao Yi-Lu, Chen Yu-Min, Liu Tong-Ye, Zhang Yi-He, Xie Jie-Ying, Zhang Jin-Feng, Zhang Han, Chen He, Peng Yu, Zhang Chun-Lei, Rau Andrew R, Hansen Kasper B, Xu Hai-Bing, Yi Feng
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.
Department of Neurology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510006, China.
Acta Pharmacol Sin. 2025 Sep 10. doi: 10.1038/s41401-025-01643-2.
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.
近期对氯胺酮快速抗抑郁作用的研究，以及对精神分裂症相关易感基因的研究，都凸显了GluN2A亚基是情绪和认知的关键调节因子。然而，急性药理学抑制含GluN2A的NMDA受体对脑微回路的具体影响以及随后的行为后果仍知之甚少。在本研究中，我们首先研究了选择性GluN2A NMDA受体抑制剂MPX-004对背内侧前额叶皮质（dmPFC）内行为的影响。在dmPFC局部施用MPX-004导致强迫游泳试验中的不动时间缩短，呈现急性抗抑郁样效应，感觉运动门控受损以及精神分裂症样表型。体内多通道记录和c-Fos染色显示，MPX-004降低了表达小白蛋白的中间神经元（PV-INs）的活性，并增加了锥体神经元（PYNs）的活性。体内膜片钳记录进一步证实，PV-IN失活导致PFC中PYN放电率升高。体外全细胞记录表明，与表达生长抑素的中间神经元（SST-INs）和PYNs相比，PV-INs接受更强的兴奋性突触输入，对突触前刺激的反应更强烈，这使得它们易受GluN2A抑制。最后，前额叶PV-INs中GluN2A的特异性敲低消除了MPX-004的行为效应，强调了GluN2A介导的PV-INs调节在这些表型中的关键作用。总之，这些发现表明PV-INs特别容易受到GluN2A抑制，导致前额叶回路去抑制，并产生抗抑郁样和精神分裂症样行为。
