Inborn errors of CACNA1A-encoded P/Q-type calcium channels impair synaptic transmission, producing early and lifelong neurological deficits, including childhood absence epilepsy, ataxia and dystonia. Whether these impairments owe their pathologies to defective channel function during the critical period for thalamic network stabilization in immature brain remains unclear. Here we show that mice with tamoxifen-induced adult-onset ablation of P/Q channel alpha subunit (iKOp/q) display identical patterns of dysfunction, replicating the inborn loss-of-function phenotypes and, therefore demonstrate that these neurological defects do not rely upon developmental abnormality. Unexpectedly, unlike the inborn model, the adult-onset pattern of excitability changes believed to be pathogenic within the thalamic network is non-canonical. Specifically, adult ablation of P/Q channels does not promote Cacna1g-mediated burst firing or T-type calcium current (IT) in the thalamocortical relay neurons; however, burst firing in thalamocortical relay neurons remains essential as iKOp/q mice generated on a Cacna1g deleted background show substantially diminished seizure generation. Moreover, in thalamic reticular nucleus neurons, burst firing is impaired accompanied by attenuated IT. Interestingly, inborn deletion of thalamic reticular nucleus-enriched, human childhood absence epilepsy-linked gene Cacna1h in iKOp/q mice reduces thalamic reticular nucleus burst firing and promotes rather than reduces seizure, indicating an epileptogenic role for loss-of-function Cacna1h gene variants reported in human childhood absence epilepsy cases. Together, our results demonstrate that P/Q channels remain critical for maintaining normal thalamocortical oscillations and motor control in the adult brain, and suggest that the developmental plasticity of membrane currents regulating pathological rhythmicity is both degenerate and age-dependent.

中文翻译：

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成年老鼠体内Cacna1a的丢失通过独特的丘脑爆发机制概括了儿童期失神癫痫。

CACNA1A编码的P / Q型钙通道的先天性错误会损害突触传递，产生早期和终生的神经功能缺损，包括儿童期癫痫，共济失调和肌张力障碍。尚不清楚这些损伤是否归因于在未成熟大脑丘脑网络稳定的关键时期内通道功能缺陷所致。在这里，我们显示具有他莫昔芬诱导的成人发作的P / Q通道α亚基（iKOp / q）消融的小鼠显示出相同的功能障碍模式，复制了先天性功能丧失的表型，因此证明这些神经系统缺陷不会依靠发育异常。出乎意料的是，与先天模型不同，在丘脑网络内被认为是致病性的兴奋性变化的成人发作模式是非典型的。具体来说，成人消融P / Q通道不会促进丘脑皮质中枢神经元中Cacna1g介导的猝发放电或T型钙电流（IT）；然而，由于在Cacna1g缺失背景上产生的iKOp / q小鼠显示癫痫发作的产​​生明显减少，因此丘脑皮质中枢神经元的爆发放电仍然必不可少。此外，在丘脑网状核神经元中，爆发放电伴随IT减弱而受损。有趣的是，iKOp / q小鼠中丘脑网状核富集的，人类童年缺乏癫痫相关基因Cacna1h的先天缺失减少了丘脑网状核的爆发并促进而不是减少了癫痫发作，这表明功能丧失的Cacna1h基因变体具有致癫痫作用报道在儿童期缺乏癫痫的病例中。一起，