Neuronal atrophy is a key feature of many neurodegenerative diseases and has often been assumed to be an early event in the progression towards neuronal death. Now, Dell'Orco et al. show that the atrophy of Purkinje neurons (PNs) that occurs in a mouse model of spinocerebellar ataxia 1 (SCA1) is a compensatory response to abnormal membrane depolarization.
The authors set out to investigate the cause of the lack of firing in the 5-week-old ATXN1(82Q) PNs. Pharmacological manipulations showed that the abnormal depolarization of PNs from 5-week-old ATXN1(82Q) mice could be reversed by blocking voltage-gated calcium channels (VGCCs). Normally, VGCC currents activate calcium-activated potassium channels, which then repolarize the membrane. Using iberiotoxin, which blocks large-conductance calcium-activated potassium (BK) channels, the authors found that evoked spikes in PNs from 5-week-old ATXN1(82Q) mice had smaller iberiotoxin-sensitive afterhyperpolarization currents (AHPs) than did spikes from control cells. This finding suggests that the unopposed VGCC current results from a loss of BK channels in the mutant cells. Indeed, immunostaining and RNA sequencing revealed that the expression of BK channels and other, subthreshold-activated potassium channels was lower in the cerebella of 5-week-old ATXN1(82Q) mice than in controls. Together, these data indicate that, at 5 weeks — before neuronal atrophy occurs — a reduction in potassium channel expression is associated with aberrant depolarization and silencing of ATXN1(82Q) PNs.
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