Astrocytes derived from ASD individuals alter behavior and destabilize neuronal activity through aberrant Ca(2+) signaling.
Astrocytes derived from ASD individuals alter behavior and destabilize neuronal activity through aberrant Ca(2+) signaling.
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DOI：
10.1038/s41380-022-01486-x
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发表时间：
2022-05
影响因子：
11
通讯作者：
Colak, Dilek
中科院分区：
文献类型：
--
作者：
Allen, Megan;Huang, Ben S.;Notaras, Michael J.;Lodhi, Aiman;Barrio-Alonso, Estibaliz;Lituma, Pablo J.;Wolujewicz, Paul;Witztum, Jonathan;Longo, Francesco;Chen, Maoshan;Greening, David W.;Klann, Eric;Ross, M. Elizabeth;Liston, Conor;Colak, Dilek
自闭症谱系障碍（ASD）的细胞机制知之甚少。累积的证据表明，异常的突触功能是这种疾病的许多特征的基础。星形胶质细胞调节几个关键的神经元过程，包括突触的形成和突触可塑性的调制。在ASD个体的死后脑组织中也发现了星形胶质细胞异常。然而，目前尚不清楚星形胶质细胞病理是否在ASD中起机械作用，而不是代偿反应。为了解决这一问题，我们将干细胞培养与移植技术相结合，以确定ASD星形胶质细胞固有的疾病特异性。我们证明，ASD星形胶质细胞诱导重复行为，以及损害记忆和长时程增强，当移植到健康的小鼠大脑。这些在体内的表型伴随着减少神经网络的活动和脊髓密度造成的ASD星形胶质细胞在体外海马神经元。移植的ASD星形胶质细胞在嵌合体脑中也表现出夸大的Ca2+波动。ASD星形胶质细胞中诱发的Ca2+反应的遗传调节调节行为和神经元活动缺陷。因此，这项研究确定了来源于ASD iPSC的星形胶质细胞足以诱导重复行为以及认知缺陷，这表明星形胶质细胞在ASD中的先前未被认识的主要作用。
The cellular mechanisms of autism spectrum disorder (ASD) are poorly understood. Cumulative evidence suggests that abnormal synapse function underlies many features of this disease. Astrocytes regulate several key neuronal processes, including the formation of synapses and the modulation of synaptic plasticity. Astrocyte abnormalities have also been identified in the postmortem brain tissue of ASD individuals. However, it remains unclear whether astrocyte pathology plays a mechanistic role in ASD, as opposed to a compensatory response. To address this, we combined stem cell culturing with transplantation techniques to determine disease-specific properties inherent to ASD astrocytes. We demonstrate that ASD astrocytes induce repetitive behavior as well as impair memory and long-term potentiation when transplanted into the healthy mouse brain. These in vivo phenotypes were accompanied by reduced neuronal network activity and spine density caused by ASD astrocytes in hippocampal neurons in vitro. Transplanted ASD astrocytes also exhibit exaggerated Ca2+ fluctuations in chimeric brains. Genetic modulation of evoked Ca2+ responses in ASD astrocytes modulates behavior and neuronal activity deficits. Thus, this study determines that astrocytes derived from ASD iPSCs are sufficient to induce repetitive behavior as well as cognitive deficit, suggesting a previously unrecognized primary role for astrocytes in ASD.
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影响因子：
25
作者：
Ballas, Nurit;Lioy, Daniel T.;Grunseich, Christopher;Mandel, Gail
通讯作者：
Mandel, Gail
影响因子：
34.7
作者：
Clarke, Laura E.;Barres, Ben A.
通讯作者：
Barres, Ben A.
影响因子：
6.2
作者：
Edmonson C;Ziats MN;Rennert OM
通讯作者：
Rennert OM
DOI：
10.1523/jneurosci.2773-06.2006
发表时间：
2006-09-27
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Billups D;Billups B;Challiss RA;Nahorski SR
通讯作者：
Nahorski SR
影响因子：
4.6
作者：
Allen M;Ghosh S;Ahern GP;Villapol S;Maguire-Zeiss KA;Conant K
通讯作者：
Conant K