Central Nervous System Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorferstr. 65, 88397 Biberach Riß, Germany.
Central Nervous System Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorferstr. 65, 88397 Biberach Riß, Germany.
Neuroscience. 2022 Aug 1;496:190-204. doi: 10.1016/j.neuroscience.2022.06.027. Epub 2022 Jun 21.
Disturbance in synaptic excitatory and inhibitory (E/I) transmission in the prefrontal cortex is considered a critical factor for cognitive dysfunction, a core symptom in schizophrenia. However, the cortical network pathophysiology induced by E/I imbalance is not well characterized, and an effective therapeutic strategy is lacking. In this study, we simulated imbalanced cortical network by using mice with parvalbumin neuron (PV) specific knockout of GluA1 (AMPA receptor subunit 1) (Gria1-PV KO) as an experimental model. Applying high-content confocal imaging and electrophysiological recordings in the medial prefrontal cortex (mPFC), we found structural and functional alterations in the local network of Gria1-PV KO mice. Additionally, we applied electroencephalography (EEG) to assess potential deficits in mismatch negativity (MMN), the standard readout in the clinic for measuring deviance detection and sensory information processing. Gria1-PV KO animals exhibited abnormal theta oscillation and MMN, which is consistent with clinical findings in cognitively impaired patients. Remarkably, we demonstrated that the glycine transporter 1 (GlyT1) inhibitor, Bitopertin, ameliorates E/I imbalance, hyperexcitability, and sensory processing malfunction in Gria1-PV KO mice. Our results suggest that PV-specific deletion of GluA1 might be an experimental approach for back translating the E/I imbalance observed in schizophrenic patients. Our work offers a systematic workflow to understand the effect of GlyT1 inhibition in restoring cortical network activity from single cells to local brain circuitry. This study highlights that selectively boosting NMDA receptor-mediated excitatory drive to enhance the network inhibitory transmission from interneurons to pyramidal neurons (PYs) is a potential therapeutic strategy for restoring E/I imbalance-associated cognitive-related abnormality.
突触兴奋性和抑制性（E/I）传递在额皮质中的紊乱被认为是认知功能障碍的一个关键因素，这是精神分裂症的核心症状。然而，E/I 失衡引起的皮质网络病理生理学尚未得到很好的描述，也缺乏有效的治疗策略。在这项研究中，我们使用特异性敲除谷氨酸能神经元（PV）上的 GluA1（AMPA 受体亚单位 1）（Gria1-PV KO）的小鼠作为实验模型，模拟不平衡的皮质网络。在中前额皮质（mPFC）中应用高内涵共聚焦成像和电生理记录，我们发现 Gria1-PV KO 小鼠局部网络存在结构和功能改变。此外，我们应用脑电图（EEG）来评估失匹配负波（MMN）的潜在缺陷，MMN 是临床上用于测量偏离检测和感觉信息处理的标准读数。Gria1-PV KO 动物表现出异常的θ振荡和 MMN，这与认知受损患者的临床发现一致。值得注意的是，我们证明甘氨酸转运体 1（GlyT1）抑制剂 Bitopertin 可改善 Gria1-PV KO 小鼠的 E/I 失衡、过度兴奋和感觉处理功能障碍。我们的结果表明，PV 特异性 GluA1 缺失可能是一种将精神分裂症患者中观察到的 E/I 失衡反向转化为实验方法。我们的工作提供了一个系统的工作流程，从单细胞到局部脑回路，了解 GlyT1 抑制对恢复皮质网络活动的影响。这项研究强调，选择性增强 NMDA 受体介导的兴奋性驱动，增强中间神经元到锥体神经元（PYs）的网络抑制性传递，是恢复与 E/I 失衡相关的认知相关异常的一种潜在治疗策略。
