Ibrahim, Mohamed F;
Boyanova, Sevda;
Cheng, Yin Chun;
Ligneul, Clemence;
Bains, Rasneer S;
Johnpulle, Tiffany C;
Lerch, Jason P;
... Becker, Esther BE; + view all
(2026)
Enhanced mGluR1 function causes motor deficits and region-specific Purkinje cell dysfunction.
Brain
, Article awaf477. 10.1093/brain/awaf477.
(In press).
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Abstract
Spinocerebellar ataxias (SCAs) are autosomal dominantly inherited neurodegenerative disorders with no effective treatment. Aberrant signalling through the metabotropic glutamate receptor (mGluR1) has been implicated in several SCAs. However, whether disease is caused through decreased or increased mGluR1 signalling remains controversial. Here, we generate the first mouse model of enhanced mGluR1 function by introducing a gain-of-function mutation (p.Y792C) that causes SCA44 in the metabotropic glutamate receptor 1 (Grm1) gene. Grm1 mutant mice recapitulate key pathophysiological aspects of SCA, including progressive motor deficits, altered climbing fibre innervation and perturbed Purkinje cell (PC) spontaneous activity. We report that changes in synaptic innervation and intrinsic PC activity upon overactive mGluR1 signalling manifest in a lobule- and disease-stage-specific manner. Our findings demonstrate that enhanced mGluR1 function is a direct and specific driver of PC dysfunction and pathology and provide a mechanism for understanding the selective vulnerability of different PC populations in SCA.
| Type: | Article |
|---|---|
| Title: | Enhanced mGluR1 function causes motor deficits and region-specific Purkinje cell dysfunction |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1093/brain/awaf477 |
| Publisher version: | https://doi.org/10.1093/brain/awaf477 |
| Language: | English |
| Additional information: | © The Author(s) 2026. Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). |
| Keywords: | cerebellum, Grm1, mGluR1, Purkinje cell, ataxia, selective vulnerability |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > UK Dementia Research Institute |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10220663 |
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