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.
Highlights
Neuronal loss in the cerebellum and its associated pathways is a consistent feature of degenerative cerebellar ataxia [1, 2]
We utilize a model of spinocerebellar ataxia type 1 (SCA1) where K+ channel dysfunction and spiking abnormalities have been linked to neurodegeneration [15, 18], and we explore the hypothesis that reduced expression of K+ channels found in Purkinje neuron dendrites results in increased dendritic excitability that contributes to dendritic degeneration
We demonstrate that a treatment strategy which targets K+ channels is able to reduce Purkinje neuron dendritic excitability, and we find that this treatment strategy improves motor performance and preserves dendrite structure in SCA1 mice
Summary
Neuronal loss in the cerebellum and its associated pathways is a consistent feature of degenerative cerebellar ataxia [1, 2]. Human autopsy studies using samples from patients with cerebellar ataxia reveal atrophy of the normally extensive dendritic arbor in surviving Purkinje neurons, suggesting a neuropathological progression which begins. Progressive changes in Purkinje neuron morphology are present in mouse models of cerebellar ataxia, where Purkinje neuron dendritic degeneration consistently precedes detectable cell loss. Motor impairment in these models typically occurs shortly before or coincident with dendritic degeneration, suggesting that dendritic degeneration may contribute to motor impairment [5,6,7]. Despite the fact that these findings point to dendritic degeneration as an early and clinically relevant process in ataxia neuropathology, the mechanisms underlying dendritic degeneration remain poorly understood
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