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

Sebastianutto, Irene LU ; Cenci, Maria Angela LU and Fieblinger, Tim LU (2017) In Neurobiology of Disease 105. p.117-131
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... (More)

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 state.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Calcium, Dendrites, Excitability, Huntington's disease, Indirect pathway, Patch clamp, Striatum, Two photon
in
Neurobiology of Disease
volume
105
pages
15 pages
publisher
Elsevier
external identifiers
  • scopus:85020191363
  • wos:000406734300010
ISSN
0969-9961
DOI
10.1016/j.nbd.2017.05.011
language
English
LU publication?
yes
id
6a8abb8c-e2bc-4f4f-a3e0-e0ddb888a18a
date added to LUP
2017-06-26 11:40:49
date last changed
2018-04-29 04:39:59
@article{6a8abb8c-e2bc-4f4f-a3e0-e0ddb888a18a,
  abstract     = {<p>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 state.</p>},
  author       = {Sebastianutto, Irene and Cenci, Maria Angela and Fieblinger, Tim},
  issn         = {0969-9961},
  keyword      = {Calcium,Dendrites,Excitability,Huntington's disease,Indirect pathway,Patch clamp,Striatum,Two photon},
  language     = {eng},
  month        = {09},
  pages        = {117--131},
  publisher    = {Elsevier},
  series       = {Neurobiology of Disease},
  title        = {Alterations of striatal indirect pathway neurons precede motor deficits in two mouse models of Huntington's disease},
  url          = {http://dx.doi.org/10.1016/j.nbd.2017.05.011},
  volume       = {105},
  year         = {2017},
}