Abstract：
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.
摘要：
小电导钙激活钾（SK）通道是众所周知的神经元兴奋性调节剂。在丘脑中心，SK2通道作为丘脑网状神经元的起搏器，在丘脑皮层回路中起关键作用。几个疾病相关基因在这些神经元中高度富集，包括已知与精神分裂症和注意力障碍有关的基因，这可能会影响神经元的放电。本研究通过在脑切片中进行全细胞膜片钳记录，评估了SK通道的药理调节在丘脑网状神经元的放电模式和固有特性中的作用。使用了两种SK正变构调节剂和一种负变构调节剂：CyPPA，分别为NS309和NS8593。通过作用于脉冲后超极化(AHP)，SK通道的负调制导致动作电位(AP)激发增加，增加了突发持续时间，并减少了突发之间的间隔。相反，CyPPA和NS309都增加了后爆发AHP，延长突发间隔，在NS309的情况下，这还导致AP射击减少。SK通道活动的改变有望改变丘脑皮质回路的功能。靶向SK通道在治疗涉及丘脑网状功能障碍的疾病如精神病和神经发育障碍方面可能是有希望的。
