Habela Christa W, Liu Shiyu, Taga Arens, Oddoye Sean, Dastgheyb Raha, Haughey Norman, Bergles Dwight E, Song Hongjun, Ming Guo-Li, Maragakis Nicholas J
Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, Baltimore, MD, USA.
Transl Psychiatry. 2025 Aug 29;15(1):329. doi: 10.1038/s41398-025-03453-w.
The chromosome 15q11.2 locus is deleted in 1.5% of patients with genetic epilepsy and confers a risk for intellectual disability and schizophrenia. Individuals with this deletion demonstrate increased cortical thickness, decreased cortical surface area and white matter abnormalities. Human induced pluripotent stem cell (iPSC)-derived neural progenitor cells from 15q11.2 deletion individuals exhibit early adhesion junction and migration abnormalities, but later neuronal development and function have not been fully assessed. Imaging studies indicating altered structure and network connectivity in the anterior brain regions and the cingulum suggest that in addition to alterations in neural progenitor dynamics, there may also be structural and functional changes within discrete networks of neurons. To explore this, we generated human forebrain cortical neurons from iPSCs derived from individuals with or without 15q11.2 deletion and used longitudinal imaging and multielectrode array analysis to evaluate neuronal development over time. 15q11.2 deleted neurons exhibited fewer connections and an increase in inhibitory neurons. Individual neurons had decreased neurite complexity and overall decreased neurite length. These structural changes were associated with a reduction in multiunit action potential generation, bursting and synchronization. The 15q11.2 deleted neurons also demonstrated specific functional deficits in glutamate- and GABA-mediated neuronal network activity and synchronization with a delay in the maturation of the inhibitory response to GABA. These data indicate that deletion of the 15q11.2 region is sufficient to impair the structural and functional maturation of cortical neuron networks, and suggest an in vitro correlate to the pathologic changes in humans with the 15q11.2 deletion.
在1.5%的遗传性癫痫患者中，15号染色体15q11.2位点发生缺失，这会增加智力残疾和精神分裂症的风险。有这种缺失的个体表现出皮质厚度增加、皮质表面积减少和白质异常。来自15q11.2缺失个体的人诱导多能干细胞（iPSC）衍生的神经祖细胞表现出早期黏附连接和迁移异常，但后期神经元发育和功能尚未得到充分评估。影像学研究表明前脑区域和扣带束的结构和网络连接发生改变，这表明除了神经祖细胞动力学改变外，神经元离散网络内也可能存在结构和功能变化。为了探究这一点，我们从有或无15q11.2缺失的个体来源的iPSC中生成了人类前脑皮质神经元，并使用纵向成像和多电极阵列分析来评估随时间的神经元发育。15q11.2缺失的神经元连接较少，抑制性神经元增加。单个神经元的神经突复杂性降低，神经突总长度减少。这些结构变化与多单位动作电位产生、爆发和同步性的降低有关。15q11.2缺失的神经元在谷氨酸和GABA介导的神经元网络活动以及同步方面也表现出特定的功能缺陷，对GABA的抑制反应成熟延迟。这些数据表明，15q11.2区域的缺失足以损害皮质神经元网络的结构和功能成熟，并提示与15q11.2缺失的人类病理变化存在体外相关性。
Zotero 插件
