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Kv3 channels in the murine lumbo-sacral spinal cord

Mullen, Pierce Nathan (2018) Kv3 channels in the murine lumbo-sacral spinal cord. PhD thesis, University of Leeds.

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Abstract

Ion channels are important in a range of physiological processes and can be targeted pharmacologically and therapeutically. Kv3 channels are voltage-gated potassium ion channels important in neuronal firing and synaptic transmission and are highly expressed in the brain and spinal cord. The main aim of this thesis was to investigate the role of Kv3 channels in the spinal cord and we did this in three ways. Using fluorescence immunohistochemistry we identified, for the first time, expression of Kv3 subunits in the murine lumbosacral spinal cord, at the level of neuronal circuitry that regulates bladder function. Specifically, some of this expression could be attributed to both excitatory and inhibitory synaptic structures closely apposed to bladder motoneurones, the final output neurones in the control of bladder function. Kv3 expression at these locations was susceptible to ageing and was reduced in aged mice. Kv3 channels were functional in synapses as Kv3 blockade with TEA increased the amplitude of the post-synaptic response. To determine the role of Kv3 channels in a function of the spinal cord, specifically, control over bladder function, we used a modulator AUT1 (Autifony Therapeutics Ltd), which is selective for Kv3 channels, Treatment with AUT1 reduced bladder output in a dose-dependent manner, acutely in young mice and chronically in aged mice suggesting involvement of Kv3 channels in bladder output. The effect of AUT1 on specific Kv3 subunits was determined in HEK expression cell lines where it was found to modulate both a previously unexplored subunit (Kv3.4a) and a physiologically relevant heteromer. In lumbosacral spinal cord slices, AUT1 suppressed the excitability of interneurones, suggesting that the reduction in bladder output could be occurring at the level of interneurones in the lumbosacral spinal cord. Modulating Kv3 channels in this way may be a viable therapeutic strategy for conditions presenting with an overactive bladder.

Item Type: Thesis (PhD)
Keywords: Voltage-gated potassium channels, spinal cord, micturition, Kv3 channels
Academic Units: The University of Leeds > Faculty of Biological Sciences (Leeds)
Depositing User: Mr Pierce Nathan Mullen
Date Deposited: 29 May 2019 09:08
Last Modified: 29 May 2019 09:08
URI: http://etheses.whiterose.ac.uk/id/eprint/24077

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