马萨诸塞州总医院Amar Sahay课题组的一项最新研究揭示了神经发育障碍患者PV神经元可塑性的认知前恢复。2026年8月12日，国际知名学术期刊《自然》发表了这一成果。

在这里，课题组人员设计了一个输入特异性翻译组筛选，以确定成人海马CA3/CA2亚区经验依赖性PV - IN可塑性基因（XPG）的调节因子。小组发现，在自闭症谱系障碍、癫痫、双相情感障碍和精神分裂症中，大量上调的候选XPG表现出单倍性不足，这表明NDD中存在经验依赖的PV IN可塑性受损。在概念验证实验中，靶向上调候选XPG，同源盒基因Meis2，在成人的NDD风险模型中，CA3/CA2 PV IN足以恢复经验依赖的PV IN可塑性。

此外，集合和锐波纹波性能和认知得到改善，癫痫发作得到抑制。因此，经验依赖的PV IN可塑性是NDD风险基因的一种趋同机制，可以在成年期重新启动，以逆转回路、网络兴奋性和认知方面的发育缺陷。

据悉，海马体在协同锥体神经元（PNs）群中形成他们的经历记忆。海马齿状节律- CA3/CA2回路中快速尖峰小白蛋白表达抑制性神经元（PV INs）通过苔藓纤维依赖的前馈抑制精确控制PN活性。PV IN协调经验依赖的内在兴奋性、突触连通性、生理和可塑性特性的变化（这里称为经验依赖的PV IN可塑性），以调节PN活动。在生命早期，当神经回路对经验高度敏感时，PV IN损伤被认为会导致网络过度兴奋性、癫痫发作和认知受损，这些都是神经发育障碍（NDD）的标志。

附：英文原文

Title: Procognitive restoration of PV neuron plasticity in neurodevelopmental disorders

Author: Shih, Yu-Tzu, Alipio, Jason Bondoc, Klaft, Zin-Juan, Green, Nathaniel, Mohapatra, Alok Nath, Goode, Travis D., Panchanatham, Muthu, Pathak, Devesh, Wong, Lai Ping, Sadreyev, Ruslan, Hyun, Jung Ho, Ahmed, Omar, Dulla, Chris, Sahay, Amar

Issue&Volume: 2026-08-12

Abstract: The hippocampus forms memories of our experiences in populations of coactive pyramidal neurons (PNs)1,2,3. Fast-spiking parvalbumin-expressing inhibitory neurons (PV INs) in the dentate gyrus–CA3/CA2 circuit of the hippocampus precisely control PN activity through mossy fibre-dependent feedforward inhibition4,5,6,7,8,9,10,11. PV INs coordinate experience-dependent changes in their intrinsic excitability, synaptic connectivity, physiology and plasticity properties9,12,13,14,15—referred to here as experience-dependent PV IN plasticity—to regulate PN activity. PV IN impairments in early life, when neural circuitry is highly sensitive to experience, are thought to result in network hyperexcitability, seizures and impaired cognition, which are hallmarks of neurodevelopmental disorders (NDDs)16,17,18. Here we designed an input-specific translatome screen to identify regulators of experience-dependent PV IN plasticity genes (XPGs) in the CA3/CA2 subregion of adult hippocampus. We demonstrate that a substantial proportion of upregulated candidate XPGs exhibit haploinsufficiency in autism spectrum disorder, epilepsies, bipolar disorder and schizophrenia, which suggests that there is impaired experience-dependent PV IN plasticity in NDDs. In proof-of-concept experiments, targeted upregulation of a candidate XPG, the homeobox gene Meis2 (ref. 19), in CA3/CA2 PV INs in an NDD risk mouse model in adulthood is sufficient to restore experience-dependent PV IN plasticity. Moreover, ensemble and sharp-wave ripple properties and cognition were improved, and seizures were suppressed. Thus, experience-dependent PV IN plasticity is a convergent mechanism for NDD risk genes that can be re-instated in adulthood to reverse developmental deficits in circuitry, network excitability and cognition.

DOI: 10.1038/s41586-026-10907-8

Source: https://www.nature.com/articles/s41586-026-10907-8