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bioRxiv · 10.1101/2020.02.20.957639

Altered synaptic plasticity and central pattern generator dysfunction in a Drosophila model of PNKD3 paroxysmal dyskinesia

Lowe, S.·Kratschmer, P.·Jepson, J. E. C.
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Abstract

BackgroundParoxysmal non-kinesigenic dyskinesia type-3 (PNKD3) has been linked to gain-of-function (GOF) mutations in the hSlo1 BK potassium channel, in particular a dominant mutation (D434G) that enhances Ca2+-sensitivity. However, while BK channels play well-known roles in regulating neurotransmitter release, it is unclear whether the D434G mutation alters neurotransmission and synaptic plasticity in vivo. Furthermore, the subtypes of movement-regulating circuits impacted by this mutation are unknown. ObjectivesWe aimed to use a larval Drosophila model of PNKD3 (sloE366G/+) to examine how BK channel GOF in dyskinesia alters synaptic properties and motor circuit function. MethodsWe used video-tracking to test for movement defects in sloE366G/+ larvae, and sharp-electrode recordings to assess the fidelity of Ca2+-dependent neurotransmitter release and short-term plasticity at the neuromuscular junction. We then combined sharp-electrode recording with ex vivo Ca2+-imaging to investigate the functionality of the central pattern generator (CPG) driving foraging behavior in sloE366G/+ larvae. ResultsWe show that the PNKD3 mutation leads to Ca2+-dependent alterations in synaptic release and paired-pulse facilitation. Furthermore, we identify robust alterations in locomotor behaviors in sloE366G/+ larvae which were mirrored by dysfunction of the upstream, movement-generating CPG in the larval ventral nerve cord. ConclusionOur results demonstrate that a BK channel GOF mutation can alter neurotransmitter release and short-term synaptic plasticity, and result in CPG dysfunction, in Drosophila larvae. These data add to a growing body of work linking paroxysmal dyskinesias to aberrant neuronal excitability and synaptic plasticity in pre-motor circuits.

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Lowe, S., Kratschmer, P., Jepson, J. E. C.. 2020-02-20. Altered synaptic plasticity and central pattern generator dysfunction in a Drosophila model of PNKD3 paroxysmal dyskinesia. https://doi.org/10.1101/2020.02.20.957639

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