Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK.
Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK.
Curr Biol. 2024 Aug 5;34(15):3488-3505.e3. doi: 10.1016/j.cub.2024.06.069. Epub 2024 Jul 24.
Critical periods are windows of heightened plasticity occurring during neurodevelopment. Alterations in neural activity during these periods can cause long-lasting changes in the structure, connectivity, and intrinsic excitability of neurons, which may contribute to the pathology of neurodevelopmental disorders. However, endogenous regulators of critical periods remain poorly defined. Here, we study this issue using a fruit fly (Drosophila) model of an early-onset movement disorder caused by BK potassium channel gain of function (BK GOF). Deploying a genetic method to place robust expression of GOF BK channels under spatiotemporal control, we show that adult-stage neuronal expression of GOF BK channels minimally disrupts fly movement. In contrast, limiting neuronal expression of GOF BK channels to a short window during late neurodevelopment profoundly impairs locomotion and limb kinematics in resulting adult flies. During this critical period, BK GOF perturbs synaptic localization of the active zone protein Bruchpilot and reduces excitatory neurotransmission. Conversely, enhancing neural activity specifically during development rescues motor defects in BK GOF flies. Collectively, our results reveal a critical developmental period for limb control in Drosophila that is influenced by BK channels and suggest that BK GOF causes movement disorders by disrupting activity-dependent aspects of synaptic development.
关键期是神经发育过程中高度可塑性发生的窗口。在此期间，神经活动的改变会导致神经元的结构、连接和内在兴奋性发生持久变化，这可能导致神经发育障碍的病理学改变。然而，关键期的内源性调节剂仍未得到很好的定义。在这里，我们使用一种果蝇（Drosophila）模型来研究这个问题，该模型由 BK 钾通道功能获得性（BK GOF）引起早期运动障碍。我们采用一种遗传方法，将 GOF BK 通道的表达置于时空控制下，结果表明成年期神经元表达 GOF BK 通道对果蝇运动的影响最小。相比之下，将 GOF BK 通道的神经元表达限制在神经发育后期的一个短暂窗口内，会严重损害成年果蝇的运动和肢体运动学。在这个关键时期，BK GOF 扰乱了 Bruchpilot 活性区蛋白的突触定位，并减少了兴奋性神经传递。相反，在发育过程中特异性增强神经活动可以挽救 BK GOF 果蝇的运动缺陷。总的来说，我们的研究结果揭示了 Drosophila 肢体控制的一个关键发育期，受 BK 通道的影响，并表明 BK GOF 通过破坏突触发育的活动依赖性方面引起运动障碍。
