Dendritic potassium channel dysfunction may contribute to dendrite degeneration in spinocerebellar ataxia type 1

Abstract

Purkinje neuron dendritic degeneration precedes cell loss in cerebellar ataxia, but the basis for dendritic vulnerability in ataxia remains poorly understood. Recent work has suggested that potassium (K+) channel dysfunction and consequent spiking abnormalities contribute to Purkinje neuron degeneration, but little attention has been paid to how K+ channel dysfunction impacts dendritic excitability and the role this may play in the degenerative process. We examined the relationship between K+ channel dysfunction, dendritic excitability and dendritic degeneration in spinocerebellar ataxia type 1 (SCA1). Examination of published RNA sequencing data from SCA1 mice revealed reduced expression of several K+ channels that are important regulators of excitability in Purkinje neuron dendrites. Patch clamp recordings in Purkinje neurons from SCA1 mice identified increased dendritic excitability in the form of enhanced back-propagation of action potentials and an increased propensity to produce dendritic calcium spikes. Dendritic excitability could be rescued by restoring expression of large-conductance calcium-activated potassium (BK) channels and activating other K+ channels with baclofen. Importantly, this treatment combination improves motor performance and mitigates dendritic degeneration in SCA1 mice. These results suggest that reduced expression of K+ channels results in persistently increased dendritic excitability at all stages of disease in SCA1, which in turn may contribute to the dendritic degeneration that precedes cell loss.

Moving Towards Therapy in SCA1: Insights from Molecular Mechanisms, Identification of Novel Targets, and Planning for Human Trials

“…Importantly, the combination of baclofen and chlorzoxazone improved motor dysfunction in the transgenic SCA1 model, and also appeared to be tolerated in patients with ataxia [52]. Baclofen alone was unable to improve motor dysfunction in this model of SCA1 [19]. Chlorzoxazone is of low potency, however, and is thus vulnerable to off-target effects.…”

“…The combined interactions between mutant ATXN1 and its binding partners alters expression of surface receptors and ion channels, working to perturb membrane excitability. In mouse models of disease, alterations in cerebellar Purkinje cell spiking due to ion channel dysfunction occurs concurrently with motor impairment, and well before cell loss [17][18][19].…”

“…In several other SCAs, Purkinje neurons exhibit altered spiking regularity or rate [17,18,48,49], a phenotype shown to arise from potassium channel dysfunction and loss of the after-hyperpolarization potential [50,51]. In mouse models of SCA1, restoration of ion channel function improves motor dysfunction [19,47,52]. Recovery of ion channel dysfunction by overexpressing potassium channels also leads to delayed Purkinje neuron degeneration, particularly when treatment is started early in disease [19,47].…”

“…In mouse models of SCA1, restoration of ion channel function improves motor dysfunction [19,47,52]. Recovery of ion channel dysfunction by overexpressing potassium channels also leads to delayed Purkinje neuron degeneration, particularly when treatment is started early in disease [19,47]. Large conductance calcium-activated (BK), small conductance calcium-activated (SK), and inwardly rectifying (Kir) potassium channels have been identified as potential therapeutic targets in SCA1.…”

A comprehensive study of the voltage gated potassium channel Kv4.3: from functional analysis to molecular dynamics modelling

“…Neuronal hyperexcitability has already been associated with a number of diseases affecting the brain, such as Alzheimer's disease, epilepsy, Parkinson's disease, and tinnitus (Chopra, Bushart, & Shakkottai, 2018). Figure 1 The proposed effect for the lack of the ISA on action potential, neuronal firing, and mitophagy in neurons.…”