Reduced GABAergic Neuron Excitability, Altered Synaptic Connectivity, and Seizures in a KCNT1 Gain-of-Function Mouse Model of Childhood Epilepsy.
Reduced GABAergic Neuron Excitability, Altered Synaptic Connectivity, and Seizures in a KCNT1 Gain-of-Function Mouse Model of Childhood Epilepsy.
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DOI：
10.1016/j.celrep.2020.108303
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发表时间：
2020-10-27
期刊：
影响因子：
8.8
通讯作者：
Weston MC
中科院分区：
文献类型：
--
作者：
Shore AN;Colombo S;Tobin WF;Petri S;Cullen ER;Dominguez S;Bostick CD;Beaumont MA;Williams D;Khodagholy D;Yang M;Lutz CM;Peng Y;Gelinas JN;Goldstein DB;Boland MJ;Frankel WN;Weston MC
K+通道的功能获得（GOF）变异导致严重的儿童癫痫，但没有机制解释K+电流增加如何导致网络过度兴奋性。在这里，我们将人类Na+激活的K+ (KNa)通道变异（KCNT1-Y796H）引入小鼠，并使用多平台方法，发现运动皮质亢奋和早发性癫痫，表型与人类患者惊人地相似。尽管这种变异增加了皮层兴奋性和抑制性神经元的KNa电流，但只有抑制性神经元，特别是那些具有非快速尖峰特性的神经元，才会增加阈下电压下的KNa电流，从而导致抑制性神经元特异性的兴奋性和动作电位（AP）产生的损伤。我们进一步观察到突触重新连接的证据，包括同型突触连通性的增加，伴随着网络的超兴奋性和超同步性。这些发现支持抑制-神经元特异性机制介导KCNT1通道GOF的致痫作用，提供细胞类型特异性电流和效应作为治疗干预的有希望的靶点。Shore等人建立了一个小鼠模型，该模型中Na+激活的K+通道基因KCNT1的GOF变异会导致儿童癫痫症。在小鼠中，KCNT1 GOF降低了皮质gaba能神经元的兴奋性，增加了同型突触连通性，导致E/I平衡被破坏，网络高兴奋性和癫痫发作。
Gain-of-function (GOF) variants in K+ channels cause severe childhood epilepsies, but there are no mechanisms to explain how increased K+ currents lead to network hyperexcitability. Here, we introduce a human Na+-activated K+ (KNa) channel variant (KCNT1-Y796H) into mice and, using a multiplatform approach, find motor cortex hyperexcitability and early-onset seizures, phenotypes strikingly similar to those of human patients. Although the variant increases KNa currents in cortical excitatory and inhibitory neurons, there is an increase in the KNa current across subthreshold voltages only in inhibitory neurons, particularly in those with non-fast-spiking properties, resulting in inhibitory-neuron-specific impairments in excitability and action potential (AP) generation. We further observe evidence of synaptic rewiring, including increases in homotypic synaptic connectivity, accompanied by network hyperexcitability and hypersynchronicity. These findings support inhibitory-neuron-specific mechanisms in mediating the epileptogenic effects of KCNT1 channel GOF, offering cell-type-specific currents and effects as promising targets for therapeutic intervention. Shore et al. generate a mouse model of a GOF variant in the Na+-activated K+ channel gene KCNT1 that causes a childhood epilepsy disorder. In mice, KCNT1 GOF reduces the excitability of cortical GABAergic neurons and increases homotypic synaptic connectivity, resulting in disrupted E/I balance, network hyperexcitability, and seizures.
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影响因子：
5.6
作者：
Anderson LL;Thompson CH;Hawkins NA;Nath RD;Petersohn AA;Rajamani S;Bush WS;Frankel WN;Vanoye CG;Kearney JA;George AL Jr
通讯作者：
George AL Jr
影响因子：
3
作者：
Jirkof, Paulin
通讯作者：
Jirkof, Paulin
影响因子：
25
作者：
Joiner, WJ;Tang, MD;Kaczmarek, LK
通讯作者：
Kaczmarek, LK
DOI：
10.1523/jneurosci.5978-08.2009
发表时间：
2009-04-29
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Chen H;Kronengold J;Yan Y;Gazula VR;Brown MR;Ma L;Ferreira G;Yang Y;Bhattacharjee A;Sigworth FJ;Salkoff L;Kaczmarek LK
通讯作者：
Kaczmarek LK
影响因子：
5.6
作者：
Baker EM;Thompson CH;Hawkins NA;Wagnon JL;Wengert ER;Patel MK;George AL Jr;Meisler MH;Kearney JA
通讯作者：
Kearney JA