Department of Psychology, The Ohio State University, 225 Psychology Building, 1835 Neil Avenue, Columbus, Ohio, 43210, USA.
Moores Cancer Center, University California, San Diego, 3855 Health Sciences Dr, La Jolla, CA, 92093, USA.
Transl Psychiatry. 2019 Feb 21;9(1):99. doi: 10.1038/s41398-019-0436-3.
Dysfunction of prefrontal parvalbumin (PV+) interneurons has been linked with severe cognitive deficits as observed in several neurodevelopmental disorders including schizophrenia. However, whether a specific aspect of PV+ neurons deregulation, or a specific molecular mechanism within PV+ neurons is responsible for cognitive deficits and other behavioral impairments remain to be determined. Here, we induced cognitive deficits and altered the prefrontal PV system in mice by exposing them neonatally to the NMDA receptor antagonist ketamine. We observed that the cognitive deficits and hyperactivity induced by neonatal ketamine were associated with a downregulation of Npas4 expression specifically in PV+ neurons. To determine whether Npas4 downregulation-induced dysfunction of PV+ neurons could be a molecular contributor to the cognitive and behavioral impairments reported after neonatal ketamine, we used a transgenic Cre-Lox approach. Reduced Npas4 expression within PV+ neurons replicates deficits in short-term memory observed after neonatal ketamine, but does not reproduce disturbances in general activity. Our data show for the first time that the brain-specific transcription factor Npas4 may be an important contributor to PV+ neurons dysfunction in neurodevelopmental disorders, and thereby could contribute to the cognitive deficits observed in diseases characterized by abnormal functioning of PV+ neurons such as schizophrenia. These findings provide a potential novel therapeutic target to rescue the cognitive impairments of schizophrenia that remain to date unresponsive to treatments.
前额叶 Parvalbumin (PV+) 中间神经元功能障碍与包括精神分裂症在内的几种神经发育障碍中观察到的严重认知缺陷有关。然而，导致认知缺陷和其他行为障碍的是 PV+ 神经元调节的特定方面，还是 PV+ 神经元内的特定分子机制，仍有待确定。在这里，我们通过在新生期使小鼠暴露于 NMDA 受体拮抗剂氯胺酮来诱导认知缺陷和改变前额叶 PV 系统。我们观察到，新生期氯胺酮引起的认知缺陷和过度活跃与 PV+ 神经元中 Npas4 表达的下调有关。为了确定 Npas4 下调诱导的 PV+ 神经元功能障碍是否是新生期氯胺酮后报道的认知和行为障碍的分子贡献者，我们使用了一种转基因 Cre-Lox 方法。PV+ 神经元中 Npas4 表达的减少复制了新生期氯胺酮后观察到的短期记忆缺陷，但不会复制一般活动的紊乱。我们的数据首次表明，脑特异性转录因子 Npas4 可能是神经发育障碍中 PV+ 神经元功能障碍的重要贡献者，从而可能导致精神分裂症等以 PV+ 神经元功能异常为特征的疾病中的认知缺陷。这些发现为迄今为止对治疗无反应的精神分裂症认知障碍提供了一个潜在的新的治疗靶点。
