Alterations of striatal indirect pathway neurons precede motor deficits in two mouse models of Huntington's disease
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 a...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2017-09-01
|
| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996117301262 |
| _version_ | 1818675844937154560 |
|---|---|
| author | Irene Sebastianutto Maria Angela Cenci Tim Fieblinger |
| author_facet | Irene Sebastianutto Maria Angela Cenci Tim Fieblinger |
| author_sort | Irene Sebastianutto |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-17T08:34:03Z |
| format | Article |
| id | doaj.art-4022ca194a44473993a15705fb31d781 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-17T08:34:03Z |
| publishDate | 2017-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-4022ca194a44473993a15705fb31d7812022-12-21T21:56:31ZengElsevierNeurobiology of Disease1095-953X2017-09-01105117131Alterations of striatal indirect pathway neurons precede motor deficits in two mouse models of Huntington's diseaseIrene Sebastianutto0Maria Angela Cenci1Tim Fieblinger2Basal Ganglia Pathophysiology Unit, Dept. of Experimental Medical Science, Lund University, 22184 Lund, SwedenBasal Ganglia Pathophysiology Unit, Dept. of Experimental Medical Science, Lund University, 22184 Lund, SwedenCorresponding author.; Basal Ganglia Pathophysiology Unit, Dept. of Experimental Medical Science, Lund University, 22184 Lund, SwedenStriatal 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.http://www.sciencedirect.com/science/article/pii/S0969996117301262Huntington's diseaseStriatumIndirect pathwayExcitabilityDendritesCalcium |
| spellingShingle | Irene Sebastianutto Maria Angela Cenci Tim Fieblinger Alterations of striatal indirect pathway neurons precede motor deficits in two mouse models of Huntington's disease Neurobiology of Disease Huntington's disease Striatum Indirect pathway Excitability Dendrites Calcium |
| title | Alterations of striatal indirect pathway neurons precede motor deficits in two mouse models of Huntington's disease |
| title_full | Alterations of striatal indirect pathway neurons precede motor deficits in two mouse models of Huntington's disease |
| title_fullStr | Alterations of striatal indirect pathway neurons precede motor deficits in two mouse models of Huntington's disease |
| title_full_unstemmed | Alterations of striatal indirect pathway neurons precede motor deficits in two mouse models of Huntington's disease |
| title_short | Alterations of striatal indirect pathway neurons precede motor deficits in two mouse models of Huntington's disease |
| title_sort | alterations of striatal indirect pathway neurons precede motor deficits in two mouse models of huntington s disease |
| topic | Huntington's disease Striatum Indirect pathway Excitability Dendrites Calcium |
| url | http://www.sciencedirect.com/science/article/pii/S0969996117301262 |
| work_keys_str_mv | AT irenesebastianutto alterationsofstriatalindirectpathwayneuronsprecedemotordeficitsintwomousemodelsofhuntingtonsdisease AT mariaangelacenci alterationsofstriatalindirectpathwayneuronsprecedemotordeficitsintwomousemodelsofhuntingtonsdisease AT timfieblinger alterationsofstriatalindirectpathwayneuronsprecedemotordeficitsintwomousemodelsofhuntingtonsdisease |