Understanding circuit-mediated vulnerability in SCA1

Description

Abstract Spinocerebellar ataxia type 1 (SCA1) is a fatal neurodegenerative disease caused by a polyglutamine (PolyQ) expansion in the Ataxin-1 protein, which is involved in regulation of transcription. ATXN1 protein is expressed throughout the central nervous system, but the expression of the mutated protein mainly affects the Purkinje cells (PCs), the sole output of the cerebellar cortex. At a circuit level there are early functional alterations involving the climbing fiber, the major excitatory inputs onto PCs, leading to impaired activation of proteins involved in synaptic transmission, but little is known about the excitation inhibition (E/I) balance of the cerebellar circuit in the context of SCA1. We show with in vivo imaging in behaving mice that there is a selective overactivation of the molecular layer interneurons (MLIs) in Sca1154/2Q that could contribute or determine the degeneration of the PCs in SCA1. Moreover, hyperconnectivity between MLIs and PCs using excitatory DREADD mimics most SCA1-specific pathological hallmarks including motor incoordination. Finally, using DREADDs we modulate the functionality of the MLIs to restore PCs functionality and ameliorate motor impairments. Our results, identify early network changes within the cerebellum of presymptomatic Sca1154/2Qmice and reveal that the modulation of synaptic component within the cerebellar cortex at any disease stage can ameliorate the motor symptoms of the pathology.

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