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Structural and functional features of medium spiny neurons in the BACHDΔN17 mouse model of Huntington’s Disease

In the BACHD mouse model of Huntington’s disease (HD), deletion of the N17 domain of the Huntingtin gene (BACHDΔN17, Q97) has been reported to lead to nuclear accumulation of mHTT and exacerbation of motor deficits, neuroinflammation and striatal atrophy (Gu et al., 2015). Here we characterized the...

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Autores principales: Goodliffe, Joseph, Rubakovic, Anastasia, Chang, Wayne, Pathak, Dhruba, Luebke, Jennifer
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310706/
https://www.ncbi.nlm.nih.gov/pubmed/32574176
http://dx.doi.org/10.1371/journal.pone.0234394
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author Goodliffe, Joseph
Rubakovic, Anastasia
Chang, Wayne
Pathak, Dhruba
Luebke, Jennifer
author_facet Goodliffe, Joseph
Rubakovic, Anastasia
Chang, Wayne
Pathak, Dhruba
Luebke, Jennifer
author_sort Goodliffe, Joseph
collection PubMed
description In the BACHD mouse model of Huntington’s disease (HD), deletion of the N17 domain of the Huntingtin gene (BACHDΔN17, Q97) has been reported to lead to nuclear accumulation of mHTT and exacerbation of motor deficits, neuroinflammation and striatal atrophy (Gu et al., 2015). Here we characterized the effect of N17 deletion on dorsolateral striatal medium spiny neurons (MSNs) in BACHDΔN17 (Q97) and BACWTΔN17 (Q31) mice by comparing them to MSNs in wildtype (WT) mice. Mice were characterized on a series of motor tasks and subsequently whole cell patch clamp recordings with simultaneous biocytin filling of MSNs in in vitro striatal slices from these mice were used to comprehensively assess their physiological and morphological features. Key findings include that: Q97 mice exhibit impaired gait and righting reflexes but normal tail suspension reflexes and normal coats while Q31 mice do not differ from WT; intrinsic membrane and action potential properties are altered -but differentially so- in MSNs from Q97 and from Q31 mice; excitatory and inhibitory synaptic currents exhibit higher amplitudes in Q31 but not Q97 MSNs, while excitatory synaptic currents occur at lower frequency in Q97 than in WT and Q31 MSNs; there is a reduced total dendritic length in Q31 -but not Q97- MSNs compared to WT, while spine density and number did not differ in MSNs in the three groups. The findings that Q31 MSNs differed from Q97 and WT neurons with regard to some physiological features and structurally suggest a novel role of the N17 domain in the function of WT Htt. The motor phenotype seen in Q97 mice was less robust than that reported in an earlier study (Gu et al., 2015), and the alterations to MSN physiological properties were largely consistent with changes reported previously in a number of other mouse models of HD. Together this study indicates that N17 plays a role in the modulation of the properties of MSNs in both mHtt and WT-Htt mice, but does not markedly exacerbate HD-like pathogenesis in the BACHD model.
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spelling pubmed-73107062020-06-26 Structural and functional features of medium spiny neurons in the BACHDΔN17 mouse model of Huntington’s Disease Goodliffe, Joseph Rubakovic, Anastasia Chang, Wayne Pathak, Dhruba Luebke, Jennifer PLoS One Research Article In the BACHD mouse model of Huntington’s disease (HD), deletion of the N17 domain of the Huntingtin gene (BACHDΔN17, Q97) has been reported to lead to nuclear accumulation of mHTT and exacerbation of motor deficits, neuroinflammation and striatal atrophy (Gu et al., 2015). Here we characterized the effect of N17 deletion on dorsolateral striatal medium spiny neurons (MSNs) in BACHDΔN17 (Q97) and BACWTΔN17 (Q31) mice by comparing them to MSNs in wildtype (WT) mice. Mice were characterized on a series of motor tasks and subsequently whole cell patch clamp recordings with simultaneous biocytin filling of MSNs in in vitro striatal slices from these mice were used to comprehensively assess their physiological and morphological features. Key findings include that: Q97 mice exhibit impaired gait and righting reflexes but normal tail suspension reflexes and normal coats while Q31 mice do not differ from WT; intrinsic membrane and action potential properties are altered -but differentially so- in MSNs from Q97 and from Q31 mice; excitatory and inhibitory synaptic currents exhibit higher amplitudes in Q31 but not Q97 MSNs, while excitatory synaptic currents occur at lower frequency in Q97 than in WT and Q31 MSNs; there is a reduced total dendritic length in Q31 -but not Q97- MSNs compared to WT, while spine density and number did not differ in MSNs in the three groups. The findings that Q31 MSNs differed from Q97 and WT neurons with regard to some physiological features and structurally suggest a novel role of the N17 domain in the function of WT Htt. The motor phenotype seen in Q97 mice was less robust than that reported in an earlier study (Gu et al., 2015), and the alterations to MSN physiological properties were largely consistent with changes reported previously in a number of other mouse models of HD. Together this study indicates that N17 plays a role in the modulation of the properties of MSNs in both mHtt and WT-Htt mice, but does not markedly exacerbate HD-like pathogenesis in the BACHD model. Public Library of Science 2020-06-23 /pmc/articles/PMC7310706/ /pubmed/32574176 http://dx.doi.org/10.1371/journal.pone.0234394 Text en © 2020 Goodliffe et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Goodliffe, Joseph
Rubakovic, Anastasia
Chang, Wayne
Pathak, Dhruba
Luebke, Jennifer
Structural and functional features of medium spiny neurons in the BACHDΔN17 mouse model of Huntington’s Disease
title Structural and functional features of medium spiny neurons in the BACHDΔN17 mouse model of Huntington’s Disease
title_full Structural and functional features of medium spiny neurons in the BACHDΔN17 mouse model of Huntington’s Disease
title_fullStr Structural and functional features of medium spiny neurons in the BACHDΔN17 mouse model of Huntington’s Disease
title_full_unstemmed Structural and functional features of medium spiny neurons in the BACHDΔN17 mouse model of Huntington’s Disease
title_short Structural and functional features of medium spiny neurons in the BACHDΔN17 mouse model of Huntington’s Disease
title_sort structural and functional features of medium spiny neurons in the bachdδn17 mouse model of huntington’s disease
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310706/
https://www.ncbi.nlm.nih.gov/pubmed/32574176
http://dx.doi.org/10.1371/journal.pone.0234394
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