eprintid: 10033858 rev_number: 24 eprint_status: archive userid: 608 dir: disk0/10/03/38/58 datestamp: 2017-11-10 11:03:17 lastmod: 2021-10-04 01:49:24 status_changed: 2017-11-10 11:03:17 type: article metadata_visibility: show creators_name: Meera, P creators_name: Pulst, S creators_name: Otis, T title: A positive feedback loop linking enhanced mGluR function and basal calcium in spinocerebellar ataxia type 2 ispublished: pub divisions: UCL divisions: B02 divisions: C08 divisions: D75 note: © Meera et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. abstract: Metabotropic glutamate receptor 1 (mGluR1) function in Purkinje neurons (PNs) is essential for cerebellar development and for motor learning and altered mGluR1 signaling causes ataxia. Downstream of mGluR1, dysregulation of calcium homeostasis has been hypothesized as a key pathological event in genetic forms of ataxia but the underlying mechanisms remain unclear. We find in a spinocerebellar ataxia type 2 (SCA2) mouse model that calcium homeostasis in PNs is disturbed across a broad range of physiological conditions. At parallel fiber synapses, mGluR1-mediated excitatory postsynaptic currents (EPSCs) and associated calcium transients are increased and prolonged in SCA2 PNs. In SCA2 PNs, enhanced mGluR1 function is prevented by buffering [Ca 2+ ] at normal resting levels while in wildtype PNs mGluR1 EPSCs are enhanced by elevated [Ca 2+ ]. These findings demonstrate a deleterious positive feedback loop involving elevated intracellular calcium and enhanced mGluR1 function, a mechanism likely to contribute to PN dysfunction and loss in SCA2. date: 2017-05-18 date_type: published official_url: http://dx.doi.org/10.7554/eLife.26377.001 oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green article_type_text: Journal Article verified: verified_manual elements_id: 1505688 doi: 10.7554/eLife.26377.001 lyricists_name: Otis, Thomas lyricists_id: TOTIS27 actors_name: Flynn, Bernadette actors_id: BFFLY94 actors_role: owner full_text_status: public publication: eLife volume: 6 article_number: e26377 issn: 2050-084X citation: Meera, P; Pulst, S; Otis, T; (2017) A positive feedback loop linking enhanced mGluR function and basal calcium in spinocerebellar ataxia type 2. eLife , 6 , Article e26377. 10.7554/eLife.26377.001 <https://doi.org/10.7554/eLife.26377.001>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10033858/1/Meera_Positive_feedback_loop.pdf