Cerebellar dysfunction in rodent models with dystonia, tremor, and ataxia

Abstract

Dystonia is a movement disorder characterized by involuntary co- or over-contractions of the muscles, which results in abnormal postures and movements. These symptoms arise from the pathophysiology of a brain-wide dystonia network. There is mounting evidence suggesting that the cerebellum is a central node in this network. For example, manipulations that target the cerebellum cause dystonic symptoms in mice, and cerebellar neuromodulation reduces these symptoms. Although numerous findings provide insight into dystonia pathophysiology, they also raise further questions. Namely, how does cerebellar pathophysiology cause the diverse motor abnormalities in dystonia, tremor, and ataxia? Here, we describe recent work in rodents showing that distinct cerebellar circuit abnormalities could define different disorders and we discuss potential mechanisms that determine the behavioral presentation of cerebellar diseases.

Cerebellar nuclei cells produce distinct pathogenic spike signatures in mouse models of ataxia, dystonia, and tremor

“…Optogenetically modulating Purkinje cell projections to cerebellar nuclei cells in a bursting pattern induced oscillatory tremor movements ( Stratton and Lorden, 1991 ; Brown et al, 2020b ). Together, these studies established that different manipulations of Purkinje cell inputs or outputs, and consequently Purkinje cell and nuclei neuron spike signals, can cause diverse behavioral deficits as they relate to disease ( White and Sillitoe, 2017 ; Brown et al, 2020b ; van der Heijden and Sillitoe, 2023 ). Given the heterogeneity and even comorbidity of these behaviors in a single disease model ( White et al, 2016a ), the main question that arises is, do these cerebellar neural signals represent unique pathophysiological signatures that can drive the predominant behavioral defects used to characterize different motor diseases?…”