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

Abstract

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.

Endocytic adaptor AP-2 maintains Purkinje cell function by balancing cerebellar parallel and climbing fiber synapses

“…CFs provide essential instructive signals for associative cerebellar learning (Silva et al, 2024). Changes in CF input occur in SCA (Barnes et al, 2011;Blake et al, 2013;Osório and White, 2023;Smeets and Verbeek, 2016) and genetic silencing of olivocerebellar synapses leads to severe motor deficit in mice (White and Sillitoe, 2017). Thus, we suggest that an almost complete loss of CF innervation as a consequence of increased Purkinje cell hyperexcitation underlies motor impairments in AP-2 cKO mice, a hypothesis that needs to be tested in future experiments.…”

Different Purkinje cell pathologies cause specific patterns of progressive ataxia in mice

“…We next studied a second progressive Purkinje cell degeneration mouse model, the PC-Sca1 mouse, a transgenic mouse line that overexpresses the human Atxn1 gene with an 82 CAG-repeat under the control of the Purkinje cell-specific Pcp2 promoter, and that models aspects of the polyQ-disorder spinocerebellar ataxia type 1 (SCA1) (Burright et al, 1995; Clark et al, 1997; White et al, 2021). These PC-Sca1 mice develop progressive gate and balance abnormalities from 5 weeks of age, while eyeblink conditioning, a cerebellar learning paradigm, is already impaired at 4 weeks (Burright et al, 1995; Clark et al, 1997; White et al, 2021; Osório et al, 2023). PC-Sca1 mice also showed progressive reduction in performance in the accelerated rotarod test going from mildly reduced performance at 5 weeks to severely impaired performance at 20 weeks (Clark et al, 1997).…”

“…The major histopathological hallmark during this time window is the somato-dendritic atrophy of Purkinje cells, starting with subtle loss in dendritic complexity at 3 weeks of age, severe shrinkage of the dendritic tree at 15 weeks of age, and retaining a minimal dendritic tree with small and occasionally heterotopic cell bodies after 25 weeks (Fig. 4A) (Clark et al, 1997; White et al, 2021; Osório et al, 2023). In contrast to PC-Ercc1 KO mice, PC-Sca1 mice maintain largely preserved innervation of the cerebellar nuclei even at 32 weeks of age (Fig.…”

“…Accordingly, many symptoms, including gait and stance deficits, can already be observed before the clinical diagnosis of cerebellar ataxia is established (Jacobi et al, 2013; Velázquez-Pérez et al, 2014a; Velázquez-Pérez et al, 2014b; Maas et al, 2015; Velázquez-Pérez et al, 2017; Kim et al, 2021; Velázquez-Pérez et al, 2021). Similarly, animal experiments have shown that eyeblink conditioning, a form of procedural learning critically depending on the cerebellum, can already be impaired in the pre-ataxia stage (Osório et al, 2023). Together with our current data, it becomes clear that many forms of cerebellar ataxia can already become manifest before overt clinical signs occur.…”

Lobule-Related Action Potential Shape- and History-Dependent Current Integration in Purkinje Cells of Adult and Developing Mice

“…show zone dependent synaptic plasticity [39,40], and are linked to neurodegenerative diseases [41,42]. Cerebellar learning in PCs results in an increased [43][44][45] or decreased [46,47] firing rate activity in relation to adaptation.…”