Modulation of a critical period for motor development in Drosophila by BK potassium channels

• Published in: Current biology Vol. 34; no. 15; pp. 3488 - 3505.e3
• Main Authors: Lowe, Simon A., Wilson, Abigail D., Aughey, Gabriel N., Banerjee, Animesh, Goble, Talya, Simon-Batsford, Nell, Sanderson, Angelina, Kratschmer, Patrick, Balogun, Maryam, Gao, Hao, Aw, Sherry S., Jepson, James E.C.
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 05.08.2024
• Subjects: BK channel; Drosophila; dyskinesia; dystonia; movement disorder; neurodevelopment; synaptic maturation; BK channel; movement disorder; neurodevelopment; Drosophila; dystonia; dyskinesia; synaptic maturation
• ISSN: 0960-9822; 1879-0445; 1879-0445
• DOI: 10.1016/j.cub.2024.06.069

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. •Gain-of-function (GOF) BK channels act during neurodevelopment to disrupt movement•GOF BK channels alter the composition of synaptic active zones•GOF BK channels reduce spontaneous neurotransmission during development•Enhancing developmental neural excitability rescues motor defects in BK GOF flies Lowe et al. show that a gain-of-function mutation in the BK potassium channel linked to movement disorders acts during a late stage of neural development to impair limb kinematics and locomotion in adult fruit flies. They further show that BK channel gain of function disrupts neurotransmission and synaptic maturation during this critical period.