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Impaired Pre-Motor Circuit Activity and Movement in a Drosophila Model of KCNMA1-Linked Dyskinesia.

Kratschmer, P; Lowe, SA; Buhl, E; Chen, K-F; Kullmann, DM; Pittman, A; Hodge, JJL; Jepson, JEC (2021) Impaired Pre-Motor Circuit Activity and Movement in a Drosophila Model of KCNMA1-Linked Dyskinesia. Mov Disord, 36 (5). pp. 1158-1169. ISSN 1531-8257 https://doi.org/10.1002/mds.28479
SGUL Authors: Pittman, Alan Michael

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Abstract

BACKGROUND: Paroxysmal dyskinesias (PxDs) are characterized by involuntary movements and altered pre-motor circuit activity. Causative mutations provide a means to understand the molecular basis of PxDs. Yet in many cases, animal models harboring corresponding mutations are lacking. Here we utilize the fruit fly, Drosophila, to study a PxD linked to a gain-of-function (GOF) mutation in the KCNMA1/hSlo1 BK potassium channel. OBJECTIVES: We aimed to recreate the equivalent BK (big potassium) channel mutation in Drosophila. We sought to determine how this mutation altered action potentials (APs) and synaptic release in vivo; to test whether this mutation disrupted pre-motor circuit function and locomotion; and to define neural circuits involved in locomotor disruption. METHODS: We generated a knock-in Drosophila model using homologous recombination. We used electrophysiological recordings and calcium-imaging to assess AP shape, neurotransmission, and the activity of the larval pre-motor central pattern generator (CPG). We used video-tracking and automated systems to measure movement, and developed a genetic method to limit BK channel expression to defined circuits. RESULTS: Neuronal APs exhibited reduced width and an enhanced afterhyperpolarization in the PxD model. We identified calcium-dependent reductions in neurotransmitter release, dysfunction of the CPG, and corresponding alterations in movement, in model larvae. Finally, we observed aberrant locomotion and dyskinesia-like movements in adult model flies, and partially mapped the impact of GOF BK channels on movement to cholinergic neurons. CONCLUSION: Our model supports a link between BK channel GOF and hyperkinetic movements, and provides a platform to dissect the mechanistic basis of PxDs. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Item Type: Article
Additional Information: © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords: BK channel, Drosophila, central pattern generator, locomotion, paroxysmal dyskinesia, pre-motor circuit, slowpoke, Drosophila, BK channel, slowpoke, paroxysmal dyskinesia, central pattern generator, pre-motor circuit, locomotion, 1103 Clinical Sciences, 1106 Human Movement and Sports Sciences, 1702 Cognitive Sciences, Neurology & Neurosurgery
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Mov Disord
ISSN: 1531-8257
Language: eng
Dates:
DateEvent
15 May 2021Published
15 January 2021Published Online
14 December 2020Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
RPG-2016-318Leverhulme Trusthttp://dx.doi.org/10.13039/501100000275
MR/P012256/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
109003/Z/15/ZWellcome Trusthttp://dx.doi.org/10.13039/100004440
WT104033AIAWellcome Trusthttp://dx.doi.org/10.13039/100004440
PubMed ID: 33449381
Web of Science ID: WOS:000607715600001
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/112909
Publisher's version: https://doi.org/10.1002/mds.28479

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