Pre-ataxic loss of intrinsic plasticity and motor learning in a mouse model of SCA1.

Spinocerebellar ataxias are neurodegenerative diseases the hallmark symptom of which is the development of ataxia due to cerebellar dysfunction. Purkinje cells (PCs), the principal neurons of the cerebellar cortex, are the main cells affected in these disorders but the sequence of pathological events leading to their dysfunction is poorly understood. Understanding the origins of PC dysfunction before it manifests is imperative to interpret the functional and behavioural consequences of cerebellar-related disorders, providing an optimal timeline for therapeutic interventions. Here, we report the cascade of events leading to PC dysfunction before the onset of ataxia in a mouse model of spinocerebellar ataxia 1. Spatiotemporal characterisation of the ATXN1[82Q] SCA1 mouse model revealed high levels of the mutant ATXN1[82Q] weeks before the onset of ataxia. The expression of the toxic protein first caused a reduction of PC intrinsic excitability, which was followed by atrophy of PC dendrite arborisation and aberrant glutamatergic signalling, finally leading to disruption of PC innervation of climbing fibers (CFs) and loss of intrinsic plasticity of PCs. Functionally, we found that deficits in eyeblink conditioning, a form of cerebellum-dependent motor learning, precede the onset of ataxia, matching the timeline of CF degeneration and reduced intrinsic plasticity. Together, our results suggest that abnormal synaptic signalling and intrinsic plasticity during the pre-ataxia stage of spinocerebellar ataxias underlie an aberrant cerebellar circuitry that anticipates the full extent of the disease severity. Furthermore, our work indicates the potential for eyeblink conditioning to be used as a sensitive tool to detect early cerebellar dysfunction as a sign of future disease.