Primary cilia TRP channel regulates hippocampal excitability.
Primary cilia TRP channel regulates hippocampal excitability.
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DOI：
10.1073/pnas.2219686120
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发表时间：
2023-05-30
影响因子：
11.1
通讯作者：
DeCaen, Paul G.
中科院分区：
文献类型：
--
作者：
Vien, Thuy N.;Ta, My C.;Kimura, Louise F.;Onay, Tuncer;DeCaen, Paul G.
初级纤毛是一种类似触角的细胞器，代表了神经科学研究的前沿知识。它们最早由邓肯和达尔在60多年前报道，尽管它们与神经发育疾病有关，但我们对其在神经元中的功能的了解有限。在这份手稿中，作者证明，初级纤毛是一个可兴奋的细胞器，富含PKD2L1离子通道。使用微电极电生理学和小鼠遗传学，作者发现纤毛中的这些通道有助于高频动作电位放电，它们的功能丧失主要影响中间神经元的兴奋性。PKD2L1表达的缺失损害小鼠的纤毛成熟，其行为表现出自闭症样特征和癫痫易感性，这可能对人类神经元纤毛病变状况有影响。多囊蛋白（PKD2、PKD2L1和PKD2L2）是瞬时受体电位家族的成员，形成纤毛离子通道。最值得注意的是，肾脏肾单位纤毛中的PKD 2失调与多囊肾病相关，但PKD 2L1在神经元中的功能尚未确定。在这份报告中，我们开发了动物模型来跟踪PKD2L1在大脑中的表达和亚细胞定位。我们发现PKD 2L1定位于从索马体顶部放射的海马神经元的初级纤毛中，并作为Ca 2+通道发挥作用。PKD2L1表达的缺失消除了初级纤毛成熟并减弱了神经元高频兴奋性，这使小鼠的癫痫易感性和自闭症谱系障碍样行为加速。中间神经元兴奋性的不成比例的损害表明，电路去抑制的基础上，这些小鼠的神经表型特征。我们的研究结果确定PKD2L1通道作为海马兴奋性的调节器和神经元初级纤毛作为脑电信号的细胞器介质。
Primary cilia are antenna-like organelles that represent a frontier of knowledge in neuroscience research. They were first reported by Duncan and Dahl more than 60 years ago, and although they are implicated in neurodevelopmental diseases, our understanding of their function in neurons is limited. In this manuscript, the authors demonstrate that the primary cilium is an excitable organelle richly populated with PKD2L1 ion channels. Using microelectrode electrophysiology and mouse genetics, the authors find that these channels in the cilia contribute to high-frequency action potential firing and their loss of function primarily impacts interneuron excitability. Loss of PKD2L1 expression impairs ciliary maturation in mice, which behaviorally exhibits autism-like features and seizure susceptibility that may have implications to human neuronal ciliopathy conditions. Polycystins (PKD2, PKD2L1, and PKD2L2) are members of the transient receptor potential family, which form ciliary ion channels. Most notably, PKD2 dysregulation in the kidney nephron cilia is associated with polycystic kidney disease, but the function of PKD2L1 in neurons is undefined. In this report, we develop animal models to track the expression and subcellular localization of PKD2L1 in the brain. We discover that PKD2L1 localizes and functions as a Ca2+ channel in the primary cilia of hippocampal neurons that apically radiate from the soma. Loss of PKD2L1 expression ablates primary ciliary maturation and attenuates neuronal high-frequency excitability, which precipitates seizure susceptibility and autism spectrum disorder–like behavior in mice. The disproportionate impairment of interneuron excitability suggests that circuit disinhibition underlies the neurophenotypic features of these mice. Our results identify PKD2L1 channels as regulators of hippocampal excitability and the neuronal primary cilia as organelle mediators of brain electrical signaling.
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影响因子：
16.6
作者：
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作者：
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