The critical role of persistent sodium current in hippocampal gamma oscillations.
The critical role of persistent sodium current in hippocampal gamma oscillations.
复制标题
持续钠电流在海马伽马振荡中的关键作用。
DOI：
10.1016/j.neuropharm.2019.107787
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发表时间：
2020
影响因子：
4.7
通讯作者：
Lee,Sang-Hun
中科院分区：
文献类型：
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作者：
Kang,Young-Jin;Clement,EthanM;Sumsky,StefanL;Xiang,Yangfei;Park,In-Hyun;Santaniello,Sabato;GreenfieldJr,LazarJohn;Garcia-Rill,Edgar;Smith,BretN;Lee,Sang-Hun
大脑中的伽马网络振荡是伽马频率范围（~30-100 Hz）内的快节奏网络振荡，在海马体中对学习、记忆和空间处理起关键作用。有证据表明，GABA能中间神经元，包括小清蛋白表达篮细胞（PVBC），通过与兴奋性细胞的突触相互作用，有助于皮质γ振荡。然而，皮质伽马振荡产生和维持的分子、细胞和电路基础在很大程度上是难以捉摸的。最近的研究表明，GABA能中间神经元和兴奋性细胞的内在和突触性质受缓慢失活或非失活钠电流（即，持续性钠电流（INaP），提示INaP参与γ振荡。在这里，我们使用药理学、光遗传学和电生理学方法测试INaP是否在海马γ振荡中起作用。我们发现INaP阻断剂苯妥英钠（40 μM和100 μM）和利鲁唑（10 μM）可减少CA 1网络中CaMKII表达细胞的光遗传学刺激诱导的γ振荡。全细胞膜片钳记录进一步表明，苯妥英（100 μM）降低了PVBC和锥体细胞的INaP和放电频率，而不改变动作电位的阈值和振幅，但增加了两种细胞类型的基强度。这些结果表明，INaPin锥体细胞和PVBCs是海马γ振荡所必需的，支持海马-中间神经元网络γ模型。苯妥英介导的海马γ振荡的调制可能是其抗惊厥疗效的机制，以及其对癫痫患者认知障碍的贡献。
Gamma network oscillations in the brain are fast rhythmic network oscillations in the gamma frequency range (~30-100 Hz), playing key roles in the hippocampus for learning, memory, and spatial processing. There is evidence indicating that GABAergic interneurons, including parvalbumin-expressing basket cells (PVBCs), contribute to cortical gamma oscillations through synaptic interactions with excitatory cells. However, the molecular, cellular, and circuit underpinnings underlying generation and maintenance of cortical gamma oscillations are largely elusive. Recent studies demonstrated that intrinsic and synaptic properties of GABAergic interneurons and excitatory cells are regulated by a slowly inactivating or non-inactivating sodium current (i.e., persistent sodium current,INaP), suggesting thatINaPis involved in gamma oscillations. Here, we tested whetherINaPplays a role in hippocampal gamma oscillations using pharmacological, optogenetic, and electrophysiological approaches. We found thatINaPblockers, phenytoin (40 μM and 100 μM) and riluzole (10 μM), reduced gamma oscillations induced by optogenetic stimulation of CaMKII-expressing cells in CA1 networks. Whole-cell patch-clamp recordings further demonstrated that phenytoin (100 μM) reducedINaPand firing frequencies in both PVBCs and pyramidal cells without altering threshold and amplitude of action potentials, but increased rheobase in both cell types. These results suggest thatINaPin pyramidal cells and PVBCs is required for hippocampal gamma oscillations, supporting a pyramidal-interneuron network gamma model. Phenytoin-mediated modulation of hippocampal gamma oscillations may be a mechanism underlying its anticonvulsant efficacy, as well as its contribution to cognitive impairments in epilepsy patients.