Small conductance calcium-activated potassium (SK) channels are well-known regulators of neuronal excitability. In the thalamic hub, SK2 channels act as pacemakers of thalamic reticular neurons, which play a key role in the thalamocortical circuit. Several disease-linked genes are highly enriched in these neurons, including genes known to be associated with schizophrenia and attentional disorders, which could affect neuronal firing. The present study assessed the effect of pharmacological modulation of SK channels in the firing pattern and intrinsic properties of thalamic reticular neurons by performing whole cell patch clamp recordings in brain slices. Two SK positive allosteric modulators and one negative allosteric modulator were used: CyPPA, NS309, and NS8593, respectively. By acting on the burst afterhyperpolarization (AHP), negative modulation of SK channels resulted in increased action potential (AP) firing, increased burst duration, and decreased intervals between bursts. Conversely, both CyPPA and NS309 increased the afterburst AHP, prolonging the interburst interval, which additionally resulted in reduced AP firing in the case of NS309. Alterations in SK channel activity would be expected to alter functioning of thalamocortical circuits. Targeting SK channels could be promising in treating disorders involving thalamic reticular dysfunction such as psychiatric and neurodevelopmental disorders.

中文翻译：

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丘脑网状核中小电导钙激活钾通道的门控

小电导钙激活钾 (SK) 通道是众所周知的神经元兴奋性调节因子。在丘脑中枢，SK2 通道充当丘脑网状神经元的起搏器，在丘脑皮质回路中发挥关键作用。这些神经元中高度富集了几种与疾病相关的基因，包括已知与精神分裂症和注意力障碍相关的基因，这些基因可能会影响神经元放电。本研究通过在脑切片中进行全细胞膜片钳记录，评估了 SK 通道药理调节对丘脑网状神经元放电模式和内在特性的影响。使用两种 SK 正变构调节剂和一种负变构调节剂：分别为 CyPPA、NS309 和 NS8593。通过作用于超极化后爆发 (AHP)，SK 通道的负调制导致动作电位 (AP) 放电增加、爆发持续时间增加以及爆发之间的间隔缩短。相反，CyPPA 和 NS309 都增加了后爆发 AHP，延长了爆发间间隔，这还导致 NS309 的 AP 发射减少。SK 通道活动的改变预计会改变丘脑皮质回路的功能。靶向 SK 通道可能有望治疗涉及丘脑网状功能障碍的疾病，例如精神疾病和神经发育障碍。