Cerebellar Development and Circuit Maturation: A Common Framework for Spinocerebellar Ataxias.

Francesca Binda,Smita Saxena,Carla Pernaci

doi:10.3389/fnins.2020.00293

Francesca Binda, Smita Saxena + Show 1 more

Open Access

https://doi.org/10.3389/fnins.2020.00293

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Abstract

Spinocerebellar ataxias (SCAs) affect the cerebellum and its afferent and efferent systems that degenerate during disease progression. In the cerebellum, Purkinje cells (PCs) are the most vulnerable and their prominent loss in the late phase of the pathology is the main characteristic of these neurodegenerative diseases. Despite the constant advancement in the discovery of affected molecules and cellular pathways, a comprehensive description of the events leading to the development of motor impairment and degeneration is still lacking. However, in the last years the possible causal role for altered cerebellar development and neuronal circuit wiring in SCAs has been emerging. Not only wiring and synaptic transmission deficits are a common trait of SCAs, but also preventing the expression of the mutant protein during cerebellar development seems to exert a protective role. By discussing this tight relationship between cerebellar development and SCAs, in this review, we aim to highlight the importance of cerebellar circuitry for the investigation of SCAs.

Highlights

Spinocerebellar ataxias (SCAs) are a large family of movement disorders characterized by the progressive loss of motor coordination, muscle tone and control, with a broad spectrum of severity ranging from mild gait and posture problems to death
Cerebellar development seems to be highly vulnerable to the expression of mutant SCA-causing molecules, and the resulting compromised cerebellar compartmentation, patterning and circuit wiring could have a direct impact on the severity of the disease
Application of exogenous Insulin-like growth factor I (IGF-I) to the cerebellum at P8 caused an increase in the percentage of Purkinje cells (PCs) displaying climbing fibers (CFs)-mediated polyinnervation in young adult mice; and no significant effect when the IGF-I signaling was augmented during the late phase of synaptic pruning (P12)

Summary

Introduction

Spinocerebellar ataxias (SCAs) are a large family of movement disorders characterized by the progressive loss of motor coordination, muscle tone and control, with a broad spectrum of severity ranging from mild gait and posture problems to death. The PolyQ expansion alters Cav2.1 physiology via decreased channel expression in PCs, concomitantly reducing P/Q type calcium channel-mediated currents in SCA6 knockin mice model.

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