Section on Critical Brain Dynamics, National Institute of Mental Health, Bethesda, MD, USA.
Department of Biology, Univ. of Maryland, College Park, MD, USA.
Transl Psychiatry. 2018 Jan 10;8(1):3. doi: 10.1038/s41398-017-0060-z.
Disturbed activity patterns in cortical networks contribute to the pathophysiology of schizophrenia (SZ). Several lines of evidence implicate NMDA receptor hypofunction in SZ, and blocking NMDA receptor signaling during early neurodevelopment produces cognitive deficits in rodent models that resemble those seen in schizophrenic patients. However, the altered network dynamics underlying these cognitive impairments largely remain to be characterized, especially at the cellular level. Here, we use in vivo two-photon calcium imaging to describe pathological dynamics, occurring in parallel with cognitive dysfunction, in a developmental NMDA receptor hypofunction model. We observed increased synchrony and specific alterations in spatiotemporal activity propagation, which could be causally linked to a previously unidentified persistent bursting phenotype. This phenotype was rescued by acute treatment with the NMDA receptor co-agonist D-serine or the GABA receptor agonist baclofen, which similarly rescued working memory performance. It was not reproduced by optogenetic inhibition of fast-spiking interneurons. These results provide novel insight into network-level abnormalities mediating the cognitive impairment induced by NMDA receptor hypofunction.
皮层网络活动模式的紊乱是导致精神分裂症（SZ）发病的病理生理学基础之一。有几方面的证据表明 N-甲基-D-天冬氨酸（NMDA）受体功能低下与 SZ 相关，而在神经发育早期阻断 NMDA 受体信号会导致啮齿类动物模型出现认知缺陷，这些缺陷类似于精神分裂症患者的认知缺陷。然而，这些认知障碍所涉及的改变的网络动力学在很大程度上仍有待研究，尤其是在细胞水平。在这里，我们使用活体双光子钙成像技术来描述发育性 NMDA 受体功能低下模型中与认知功能障碍同时发生的病理性动力学。我们观察到同步性增加和时空活动传播的特定改变，这可能与先前未识别的持续爆发表型有因果关系。这种表型可以通过急性 NMDA 受体共激动剂 D-丝氨酸或 GABA 受体激动剂巴氯芬处理得到挽救，而这两种处理方法也同样挽救了工作记忆表现。光遗传学抑制快棘神经元并不能复制这种表型。这些结果为 NMDA 受体功能低下诱导的认知障碍的网络水平异常提供了新的见解。
