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

Irene Sebastianutto; Maria Angela Cenci; Tim Fieblinger

doi:10.1016/j.nbd.2017.05.011

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

Standard

Alterations of striatal indirect pathway neurons precede motor deficits in two mouse models of Huntington's disease. / Sebastianutto, Irene; Cenci, Maria Angela; Fieblinger, Tim.

In: NEUROBIOL DIS, Vol. 105, 09.2017, p. 117-131.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Sebastianutto, I, Cenci, MA & Fieblinger, T 2017, 'Alterations of striatal indirect pathway neurons precede motor deficits in two mouse models of Huntington's disease', NEUROBIOL DIS, vol. 105, pp. 117-131. https://doi.org/10.1016/j.nbd.2017.05.011

APA

Sebastianutto, I., Cenci, M. A., & Fieblinger, T. (2017). Alterations of striatal indirect pathway neurons precede motor deficits in two mouse models of Huntington's disease. NEUROBIOL DIS, 105, 117-131. https://doi.org/10.1016/j.nbd.2017.05.011

Vancouver

Sebastianutto I, Cenci MA, Fieblinger T. Alterations of striatal indirect pathway neurons precede motor deficits in two mouse models of Huntington's disease. NEUROBIOL DIS. 2017 Sep;105:117-131. https://doi.org/10.1016/j.nbd.2017.05.011

Bibtex

@article{b80d9efe59434e118a490fe58dede06a,

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

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 state.",

keywords = "Action Potentials/drug effects, Animals, Cadmium Chloride/pharmacology, Cesium/pharmacology, Chlorides/pharmacology, Corpus Striatum/pathology, Dendrites/metabolism, Disease Models, Animal, Exploratory Behavior/physiology, Huntingtin Protein/genetics, Huntington Disease/complications, Mice, Mice, Inbred C57BL, Mice, Transgenic, Movement Disorders/etiology, Neurons/drug effects, Potassium/pharmacology, Psychomotor Performance/physiology, Sodium Channel Blockers/pharmacology, Tetrodotoxin/pharmacology, Trinucleotide Repeat Expansion/genetics",

author = "Irene Sebastianutto and Cenci, {Maria Angela} and Tim Fieblinger",

year = "2017",

month = sep,

doi = "10.1016/j.nbd.2017.05.011",

language = "English",

volume = "105",

pages = "117--131",

journal = "NEUROBIOL DIS",

issn = "0969-9961",

publisher = "Academic Press Inc.",

}

RIS

TY - JOUR

T1 - Alterations of striatal indirect pathway neurons precede motor deficits in two mouse models of Huntington's disease

AU - Sebastianutto, Irene

AU - Cenci, Maria Angela

AU - Fieblinger, Tim

PY - 2017/9

Y1 - 2017/9

N2 - 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.

AB - 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.

KW - Action Potentials/drug effects

KW - Animals

KW - Cadmium Chloride/pharmacology

KW - Cesium/pharmacology

KW - Chlorides/pharmacology

KW - Corpus Striatum/pathology

KW - Dendrites/metabolism

KW - Disease Models, Animal

KW - Exploratory Behavior/physiology

KW - Huntingtin Protein/genetics

KW - Huntington Disease/complications

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Transgenic

KW - Movement Disorders/etiology

KW - Neurons/drug effects

KW - Potassium/pharmacology

KW - Psychomotor Performance/physiology

KW - Sodium Channel Blockers/pharmacology

KW - Tetrodotoxin/pharmacology

KW - Trinucleotide Repeat Expansion/genetics

U2 - 10.1016/j.nbd.2017.05.011

DO - 10.1016/j.nbd.2017.05.011

M3 - SCORING: Journal article

C2 - 28578004

VL - 105

SP - 117

EP - 131

JO - NEUROBIOL DIS

JF - NEUROBIOL DIS

SN - 0969-9961

ER -