Cortical circuit alterations precede motor impairments in Huntington’s disease mice
| Autor: | Sara Gutiérrez-Ángel, Elena Katharina Schulz-Trieglaff, Fabian Hosp, Kerstin Voelkl, Ruediger Klein, Matthias Mann, Jakob M. Bader, Irina Dudanova, Sabine Liebscher, Johanna Burgold, Thomas Arzberger |
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| Rok vydání: | 2019 |
| Předmět: |
physiopathology [Huntington Disease]
Male 0301 basic medicine Dendritic spine pathology [Motor Disorders] Motor Disorders physiopathology [Motor Disorders] lcsh:Medicine Mice Transgenic Striatum Biology Neural circuits Article Mice 03 medical and health sciences 0302 clinical medicine Huntington's disease Cortex (anatomy) medicine Animals metabolism [Huntington Disease] metabolism [Motor Disorders] Promoter Regions Genetic lcsh:Science Huntingtin Protein Multidisciplinary Neocortex lcsh:R genetics [Huntingtin Protein] medicine.disease 3. Good health Mice Inbred C57BL Disease Models Animal Huntington Disease 030104 developmental biology medicine.anatomical_structure Visual cortex pathology [Huntington Disease] genetics [Promoter Regions Genetic] metabolism [Huntingtin Protein] Motor cortex lcsh:Q Female Primary motor cortex ddc:600 Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Scientific Reports Scientific reports 9(1), 6634 (2019). doi:10.1038/s41598-019-43024-w Scientific Reports, Vol 9, Iss 1, Pp 1-13 (2019) |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-019-43024-w |
| Popis: | Huntington’s disease (HD) is a devastating hereditary movement disorder, characterized by degeneration of neurons in the striatum and cortex. Studies in human patients and mouse HD models suggest that disturbances of neuronal function in the neocortex play an important role in disease onset and progression. However, the precise nature and time course of cortical alterations in HD have remained elusive. Here, we use chronic in vivo two-photon calcium imaging to longitudinally monitor the activity of identified single neurons in layer 2/3 of the primary motor cortex in awake, behaving R6/2 transgenic HD mice and wildtype littermates. R6/2 mice show age-dependent changes in cortical network function, with an increase in activity that affects a large fraction of cells and occurs rather abruptly within one week, preceeding the onset of motor defects. Furthermore, quantitative proteomics demonstrate a pronounced downregulation of synaptic proteins in the cortex, and histological analyses in R6/2 mice and human HD autopsy cases reveal a reduction in perisomatic inhibitory synaptic contacts on layer 2/3 pyramidal cells. Taken together, our study provides a time-resolved description of cortical network dysfunction in behaving HD mice and points to disturbed excitation/inhibition balance as an important pathomechanism in HD. |
| Databáze: | OpenAIRE |
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