In Vivo Analysis of the Climbing Fiber-Purkinje Cell Circuit in SCA2-58Q Transgenic Mouse Model

Abstract

Cerebellar Purkinje cells (PCs) and cerebellar pathways are primarily affected in many autosomal dominant cerebellar ataxias. PCs generate complex spikes (CS) in vivo when activated by climbing fiber (CF) which rise from the inferior olive. In this study, we investigated the functional state of the CF-PC circuitry in the transgenic mouse model of spinocerebellar ataxia type 2 (SCA2), a polyglutamine neurodegenerative genetic disease. In our experiments, we used an extracellular single-unit recording method to compare the PC activity pattern and the CS shape in age-matched wild-type mice and SCA2-58Q transgenic mice. We discovered no alterations in the CS properties of PCs in aging SCA2 mice. To examine the integrity of the olivocerebellar pathway, we applied harmaline, an alkaloid that acts directly on the inferior olive neurons. The pharmacological stimulation of olivocerebellar circuit by harmaline uncovered disturbances in SCA2-58Q PC activity pattern and in the complex spike shape when compared with age-matched wild-type cells. The abnormalities in the CF-PC circuitry were aggravated with age. We propose that alterations in CF-PC circuitry represent one of potential causes of ataxic symptoms in SCA2 and in other SCAs.

Molecular Mechanisms and Therapeutics for Spinocerebellar Ataxia Type 2

“…At 24 weeks of age, significant loss of the cerebellar PCs was observed in these mice together with a progressive loss of calbindin-28k that represents a marker for neuronal dysfunction [21]. Disturbances of the electrophysiological functions have been reported in these mice in the studies on the cerebellar slices [22,125] and also in in vivo studies [126,127]. Another SCA2 mouse model was a transgenic line SCA2-75Q that expresses a human full-length version of ATXN2 under the control of the endogenous SCA2 promoter.…”

“…At the same time, the PC generates the simple spikes responding to the excitatory potentials produced by the PF [176,195,196]. The pharmacological stimulation of the olivocerebellar circuit by harmaline, an alkaloid that acts directly on the inferior olive neurons, uncovered the disturbances in the SCA2-58Q PC activity pattern in vivo and in the CS shape when compared with the age-matched WT cells [127]. The abnormalities in the CF-PC circuitry were aggravated with age.…”

“…The abnormalities in the CF-PC circuitry were aggravated with age. Thus, it was proposed that the alterations in the CF-PC circuitry represent 1 of the potential causes of ataxic symptoms in SCA2 and in other SCAs [127].…”

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

“…The expression of the mutant ATXN1 in SCA1 PCs or ATXN2 in SCA2 PCs reduced their firing frequency (Hansen et al, 2011;Dell'Orco et al, 2015) and this decrease was also associated with an increase in PC firing variability in the SCA2 mouse model (Kasumu et al, 2012). Furthermore, in vivo analysis of complex spike activity in SCA2 mice revealed a reduction in the complex spike frequency in response to pharmacological IO stimulation by systemic harmaline injection (Egorova et al, 2018).…”

Role of Microglia in Ataxias

“…These results imply that microglia have profound control over the pruning and development of synaptic inputs to Purkinje cells [31]. Therefore, microglia may be a potential therapeutic target for ataxias in which developmental Purkinje neuron synaptic pruning is effected, such as SCA1, SCA2, SCA14, and multiple system atrophy [73,[77][78][79][80].…”