Ankyrin-G regulates forebrain connectivity and network synchronization via interaction with GABARAP
Ankyrin-G regulates forebrain connectivity and network synchronization via interaction with GABARAP
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Ankyrin-G 通过与 GABARAP 相互作用调节前脑连接和网络同步。
DOI：
10.1038/s41380-018-0308-x
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发表时间：
2020-11-01
影响因子：
11
通讯作者：
Jenkins, P. M.
中科院分区：
文献类型：
--
作者：
Nelson, A. D.;Caballero-Floran, R. N.;Jenkins, P. M.
GABA能回路对于脑网络的同步化和高阶功能至关重要。这种回路的缺陷与神经精神疾病有关，包括双相情感障碍、精神分裂症和自闭症。在培养的神经元中的工作已经表明，在锥体神经元的轴突起始段和体树突结构域上的GABA能突触的调节中，锚定蛋白-G起关键作用，其中它直接与GABA（A）受体相关蛋白（GABARAP）相互作用以稳定细胞表面GABA（A）受体。在这里，我们产生了一个基因敲入小鼠模型，表达一个突变，消除了ankle-G/GABARAP相互作用（Ank 3 W1989 R），以了解如何ankle-G和GABARAP调节GABA能电路在体内。我们发现Ank 3 W1989 R小鼠前脑GABA能突触显著减少，导致锥体细胞过度兴奋和网络同步中断。此外，我们确定了锥体细胞树突棘和轴突起始段的变化与过度兴奋的补偿一致。最后，我们确定了ANK 3 W1989 R变异在一个家庭与双相情感障碍，表明这种变异在疾病中的潜在作用。我们的研究结果强调了ANK 3-G在调节前脑回路中的重要性，并为ANK 3功能缺失变体如何导致人类疾病提供了新的见解。
GABAergic circuits are critical for the synchronization and higher order function of brain networks. Defects in this circuitry are linked to neuropsychiatric diseases, including bipolar disorder, schizophrenia, and autism. Work in cultured neurons has shown that ankyrin-G plays a key role in the regulation of GABAergic synapses on the axon initial segment and somatodendritic domain of pyramidal neurons, where it interacts directly with the GABA(A) receptor-associated protein (GABARAP) to stabilize cell surface GABA(A) receptors. Here, we generated a knock-in mouse model expressing a mutation that abolishes the ankyrin-G/GABARAP interaction (Ank3 W1989R) to understand how ankyrin-G and GABARAP regulate GABAergic circuitry in vivo. We found that Ank3 W1989R mice exhibit a striking reduction in forebrain GABAergic synapses resulting in pyramidal cell hyperexcitability and disruptions in network synchronization. In addition, we identified changes in pyramidal cell dendritic spines and axon initial segments consistent with compensation for hyperexcitability. Finally, we identified the ANK3 W1989R variant in a family with bipolar disorder, suggesting a potential role of this variant in disease. Our results highlight the importance of ankyrin-G in regulating forebrain circuitry and provide novel insights into how ANK3 loss-of-function variants may contribute to human disease.