VA Boston Healthcare System, West Roxbury, MA, USA.
Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
Sci Rep. 2021 Apr 27;11(1):9031. doi: 10.1038/s41598-021-88428-9.
Abnormalities in electroencephalographic (EEG) biomarkers occur in patients with schizophrenia and those clinically at high risk for transition to psychosis and are associated with cognitive impairment. Converging evidence suggests N-methyl-D-aspartate receptor (NMDAR) hypofunction plays a central role in the pathophysiology of schizophrenia and likely contributes to biomarker impairments. Thus, characterizing these biomarkers is of significant interest for early diagnosis of schizophrenia and development of novel treatments. We utilized in vivo EEG recordings and behavioral analyses to perform a battery of electrophysiological biomarkers in an established model of chronic NMDAR hypofunction, serine racemase knockout (SRKO) mice, and their wild-type littermates. SRKO mice displayed impairments in investigation-elicited gamma power that corresponded with reduced short-term social recognition and enhanced background (pre-investigation) gamma activity. Additionally, SRKO mice exhibited sensory gating impairments in both evoked-gamma power and event-related potential amplitude. However, other biomarkers including the auditory steady-state response, sleep spindles, and state-specific power spectral density were generally neurotypical. In conclusion, SRKO mice demonstrate how chronic NMDAR hypofunction contributes to deficits in certain translationally-relevant EEG biomarkers altered in schizophrenia. Importantly, our gamma band findings suggest an aberrant signal-to-noise ratio impairing cognition that occurs with NMDAR hypofunction, potentially tied to impaired task-dependent alteration in functional connectivity.
脑电图 (EEG) 生物标志物异常发生在精神分裂症患者和那些临床上有向精神病转化高风险的患者中，并且与认知障碍有关。越来越多的证据表明，N-甲基-D-天冬氨酸受体 (NMDAR) 功能低下在精神分裂症的病理生理学中起着核心作用，并且可能导致生物标志物受损。因此，这些生物标志物的特征对于精神分裂症的早期诊断和新疗法的开发具有重要意义。我们利用体内 EEG 记录和行为分析，在慢性 NMDAR 功能低下的建立模型中，即丝氨酸 racemase 敲除 (SRKO) 小鼠及其野生型同窝仔鼠中，进行了一系列电生理生物标志物的检测。SRKO 小鼠表现出探究诱发的伽马功率受损，这与短期社会识别能力下降和背景（预探究）伽马活动增强有关。此外，SRKO 小鼠在诱发伽马功率和事件相关电位幅度方面均表现出感觉门控障碍。然而，其他生物标志物，包括听觉稳态反应、睡眠梭形波和状态特异性功率谱密度，通常是神经典型的。总之，SRKO 小鼠表明慢性 NMDAR 功能低下如何导致某些与精神分裂症相关的 EEG 生物标志物缺陷。重要的是，我们的伽马波段研究结果表明，NMDAR 功能低下会导致认知能力的异常信号噪声比降低，这可能与功能连接的依赖性改变受损有关。
