Aberrant Cerebellar Circuitry in the Spinocerebellar Ataxias

Abstract

The spinocerebellar ataxias (SCAs) are a heterogeneous group of neurodegenerative diseases that share convergent disease features. A common symptom of these diseases is development of ataxia, involving impaired balance and motor coordination, usually stemming from cerebellar dysfunction and neurodegeneration. For most spinocerebellar ataxias, pathology can be attributed to an underlying gene mutation and the impaired function of the encoded protein through loss or gain-of-function effects. Strikingly, despite vast heterogeneity in the structure and function of disease-causing genes across the SCAs and the cellular processes affected, the downstream effects have considerable overlap, including alterations in cerebellar circuitry. Interestingly, aberrant function and degeneration of Purkinje cells, the major output neuronal population present within the cerebellum, precedes abnormalities in other neuronal populations within many SCAs, suggesting that Purkinje cells have increased vulnerability to cellular perturbations. Factors that are known to contribute to perturbed Purkinje cell function in spinocerebellar ataxias include altered gene expression resulting in altered expression or functionality of proteins and channels that modulate membrane potential, downstream impairments in intracellular calcium homeostasis and changes in glutamatergic input received from synapsing climbing or parallel fibers. This review will explore this enhanced vulnerability and the aberrant cerebellar circuitry linked with it in many forms of SCA. It is critical to understand why Purkinje cells are vulnerable to such insults and what overlapping pathogenic mechanisms are occurring across multiple SCAs, despite different underlying genetic mutations. Enhanced understanding of disease mechanisms will facilitate the development of treatments to prevent or slow progression of the underlying neurodegenerative processes, cerebellar atrophy and ataxic symptoms.

Keywords: Purkinje cell dysfunction; Purkinje cell vulnerability; cerebellar circuitry; cerebellar pathophysiology; disease mechanisms; neurodegeneration; spinocerebellar ataxia.

FIGURE 1

Schematic representation of cerebellar afferents and efferents. (A) Normal function of Purkinje cells results in balanced excitation and inhibition in cerebellar circuitry. (B) Reduced excitatory input from glutamatergic climbing fibers, due to shortened length or impaired functionality, can decrease Purkinje cell firing, resulting in disinhibition of the DCN-thalamus-motor cortex circuit. (C) Increased excitatory input from parallel and climbing fibers, due to increased synaptic connections or increased glutamate signaling within the Purkinje cell synapse, can increase Purkinje cell firing, resulting in inhibition of the DCN-thalamus-motor cortex circuit. Excitatory inputs are highlighted in green, with inhibitory inputs highlighted in red. Black inputs can be either inhibitory or excitatory.

FIGURE 2

Many forms of spinocerebellar ataxia are attributed to mutations in intracellular calcium signaling, glutamate release or the PKC pathway, which form multiple positive feedback loops. Disruption of calcium and glutamate signaling is hypothesized to initiate Purkinje cell dysfunction, resulting in ataxia and eventual cell death. Diseases indicated in red are reported to have dysfunction of this component of the signaling pathway.

FIGURE 3

The mGluR-Ca²⁺ hypothesis of SCA pathogenesis. Increases in glutamatergic signaling consequently increase intracellular calcium concentrations via two distinct pathways. Firstly, glutamate binds with AMPA and NMDA receptors, eliciting neuronal depolarization and influx of calcium. Secondly, glutamate binds with mGluR1 receptors, causing activation of the PKCγ pathway, which increases intracellular calcium concentrations via activation of IP3R1 and TRPC3.