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