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Alterations of striatal indirect pathway neurons precede motor deficits in two mouse models of Huntington's disease

Sebastianutto, Irene, Cenci, Maria Angela, Fieblinger, Tim·2017·Neurobiology of Disease
DOI 10.1016/j.nbd.2017.05.011
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Abstract

Striatal neurons forming the indirect pathway (iSPNs) are particularly vulnerable in Huntington's disease (HD). In this study we set out to investigate morphological and physiological alterations of iSPNs in two mouse models of HD with relatively slow disease progression (long CAG repeat R6/2 and zQ175-KI). Both were crossed with a transgenic mouse line expressing eGFP in iSPNs. Using the open-field and rotarod tests, we first defined two time points in relation to the occurrence of motor deficits in each model. Then, we investigated electrophysiological and morphological properties of iSPNs at both ages. Both HD models exhibited increased iSPN excitability already before the onset of motor deficits, associated with a reduced number of primary dendrites and decreased function of Kir- and voltage-gated potassium channels. Alterations that specifically occurred at symptomatic ages included increased calcium release by back-propagating action potentials in proximal dendrites, due to enhanced engagement of intracellular calcium stores. Moreover, motorically impaired mice of both HD models showed a reduction in iSPN spine density and progressive formation of huntingtin (Htt) aggregates in the striatum. Our study therefore reports iSPN-specific alterations relative to the development of a motor phenotype in two different mouse models of HD. While some alterations occur early and are partly non-progressive, others potentially provide a pathophysiological marker of an overt disease s…

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  • Reduced striatal DRD2 was consistently demonstrated in patients and murine models and its dysregulation is a sensitive measure of HD pathology.

    “In fact, reduced striatal DRD2 was consistently demonstrated in patients 45,46,47,48,49 and murine models 27,35,50,51 and its dysregulation is a sensitive measure of HD pathology 37 .”

    From SREBP2 gene therapy targeting striatal astrocytes ameliorates Huntington’s disease phenotypes (2021) · cites this paper as [46]

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Metadata

Authors
Sebastianutto, I., Cenci, M. A., & Fieblinger, T.
Venue
Neurobiology of Disease
Publisher
Elsevier BV
Published
2017-09
Volume
105
Pages
117-131
ISSN
0969-9961
DOI
10.1016/j.nbd.2017.05.011
Cited by
36
References
4
Language
en
Licence
Funders
  • Segerfalk Foundation
  • Rosenberg Foundation
  • Swedish Brain Foundation
  • Lund University
  • Seventh Framework Programme
  • Swedish Governmental Funding for Clinical Research (43301)
  • Swedish Research Council (2016-01307)
  • Åhlen-Foundation
  • Olle Engkvist Foundation
  • Basal Ganglia Disorders Linneaus Consortium

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