Mental Health Center and Psychiatric Laboratory, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, 610041, China.
West China Brain Research Center, West China Hospital of Sichuan University, Chengdu, 610041, China.
Neurosci Bull. 2020 Feb;36(2):97-109. doi: 10.1007/s12264-019-00416-2. Epub 2019 Aug 6.
The current study was designed to explore how disruption of specific molecular circuits in the cerebral cortex may cause sensorimotor cortico-striatal community structure deficits in both a mouse model and patients with schizophrenia. We used prepulse inhibition (PPI) and brain structural and diffusion MRI scans in 23 mice with conditional ErbB4 knockout in parvalbumin interneurons and 27 matched controls. Quantitative real-time PCR was used to assess the differential levels of GABA-related transcripts in brain regions. Concurrently, we measured structural and diffusion MRI and the cumulative contribution of risk alleles in the GABA pathway genes in first-episode treatment-naïve schizophrenic patients (n = 117) and in age- and sex-matched healthy controls (n = 86). We present the first evidence of gray and white matter impairment of right sensorimotor cortico-striatal networks and reproduced the sensorimotor gating deficit in a mouse model of schizophrenia. Significant correlations between gray matter volumes (GMVs) in the somatosensory cortex and PPI as well as glutamate decarboxylase 1 mRNA expression were found in controls but not in knockout mice. Furthermore, these findings were confirmed in a human sample in which we found significantly decreased gray and white matter in sensorimotor cortico-striatal networks in schizophrenic patients. The psychiatric risk alleles of the GABA pathway also displayed a significant negative correlation with the GMVs of the somatosensory cortex in patients. Our study identified that ErbB4 ablation in parvalbumin interneurons induced GABAergic dysregulation, providing valuable mechanistic insights into the sensorimotor cortico-striatal community structure deficits associated with schizophrenia.
本研究旨在探索大脑皮层特定分子回路的破坏如何导致小鼠模型和精神分裂症患者的感觉运动皮质纹状体社区结构缺陷。我们使用条件性 ErbB4 敲除在小脑浦肯野细胞间神经元中的预脉冲抑制（PPI）和大脑结构及扩散 MRI 扫描，对 23 只小鼠和 27 只匹配的对照进行研究。使用定量实时 PCR 评估大脑区域 GABA 相关转录物的差异水平。同时，我们测量了结构和扩散 MRI 以及 GABA 途径基因的风险等位基因在首次发作未经治疗的精神分裂症患者（n=117）和年龄及性别匹配的健康对照者（n=86）中的累积贡献。我们首次提供了右侧感觉运动皮质纹状体网络的灰质和白质损伤的证据，并在精神分裂症的小鼠模型中重现了感觉运动门控缺陷。在对照组中，感觉皮层的灰质体积（GMV）与 PPI 以及谷氨酸脱羧酶 1 mRNA 表达之间存在显著相关性，但在敲除小鼠中则没有。此外，在人类样本中也得到了证实，我们发现精神分裂症患者的感觉运动皮质纹状体网络中的灰质和白质明显减少。GABA 途径的精神病风险等位基因也与患者感觉皮层的 GMV 呈显著负相关。我们的研究确定了小脑浦肯野细胞间神经元中的 ErbB4 缺失诱导了 GABA 能失调，为与精神分裂症相关的感觉运动皮质纹状体社区结构缺陷提供了有价值的机制见解。
