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.
(Less)
- author
- Sebastianutto, Irene
LU
; Cenci, Maria Angela
LU
and Fieblinger, Tim
LU
- organization
- publishing date
- 2017-09-01
- 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
-
- pmid:28578004
- wos:000406734300010
- scopus:85020191363
- 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
- 2024-04-28 14:56:27
@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}},
keywords = {{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}},
doi = {{10.1016/j.nbd.2017.05.011}},
volume = {{105}},
year = {{2017}},
}