Enhanced GABAergic Inhibition of Cholinergic Interneurons in the zQ175+/- Mouse Model of Huntington's Disease.

Sean Austin O Lim,D James Surmeier

doi:10.3389/fnsys.2020.626412

Abstract

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that initially manifests itself in the striatum. How intrastriatal circuitry is altered by the disease is poorly understood. To help fill this gap, the circuitry linking spiny projection neurons (SPNs) to cholinergic interneurons (ChIs) was examined using electrophysiological and optogenetic approaches in ex vivo brain slices from wildtype mice and zQ175+/− models of HD. These studies revealed a severalfold enhancement of GABAergic inhibition of ChIs mediated by collaterals of indirect pathway SPNs (iSPNs), but not direct pathway SPNs (dSPNs). This cell-specific alteration in synaptic transmission appeared in parallel with the emergence of motor symptoms in the zQ175+/− model. The adaptation had a presynaptic locus, as it was accompanied by a reduction in paired-pulse ratio but not in the postsynaptic response to GABA. The alterations in striatal GABAergic signaling disrupted spontaneous ChI activity, potentially contributing to the network dysfunction underlying the hyperkinetic phase of HD.

Highlights

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG expansion in the Huntingtin gene (McColgan and Tabrizi, 2018)
The locus of the change was presynaptic, as the enhancement in GABAergic transmission was accompanied by an elevation of release probability. These results suggest that indirect pathway SPNs (iSPNs) hypoexcitability in the zQ175 HD model triggers synaptic adaptations that serve to compensate for the activity deficit
In zQ175+/− het mice and wildtype littermate controls, an adeno-associated virus (AAV) was stereotaxically injected into the dorsolateral striatum and 2–4 weeks later mice were sacrificed and ex vivo brain slices prepared for study using standard methodologies

Summary

Introduction

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG expansion in the Huntingtin gene (McColgan and Tabrizi, 2018). The disease is characterized by progressive cognitive disability and deterioration of motor control (Ross and Tabrizi, 2011). In adult onset HD, early in the course of the disease, hyperkinetic motor symptoms, like chorea, typically predominate. These manifestations of the disease are supplanted by hypokinetic deficits, like bradykinesia and dystonia. The motor symptoms of HD are attributable in large measure to pathology in the striatum, a key structure of the basal ganglia (Waldvogel et al, 2015; Plotkin and Goldberg, 2018). SPNs can be divided into two classes based upon their axonal projections: indirect pathway SPNs (iSPNs) and direct pathway SPNs (dSPNs). In HD, iSPNs are vulnerable and manifest signs of hypoexcitability early in the course of the human disease and early in the evolution

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