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Open access
Neurobiology of Disease, volume 154, pages 105340

Chronic optogenetic stimulation of Bergman glia leads to dysfunction of EAAT1 and Purkinje cell death, mimicking the events caused by expression of pathogenic ataxin-1

Belozor Olga S 1
Mozhei Oleg 2
Yakovleva Dariya A 3
Potapenko Ilia V 4
Smolnikova Marina
Salmin Vladimir V 5
Salmina Alla B.
Hirai Hirokazu 6
Teschemacher Anja G. 7
Kasparov Sergey 2, 7
Publication typeJournal Article
Publication date2021-07-01
Quartile SCImago
Q1
Quartile WOS
Q1
Impact factor6.1
ISSN09699961, 1095953X
Neurology
Abstract
Bergmann glia (BG) are highly specialized radial astrocytes of the cerebellar cortex, which play a key role in the uptake of synaptic glutamate via the excitatory amino acid transporter EAAT1. Multiple lines of evidence suggest that in cerebellar neurodegenerative diseases reactive BG has a negative impact on neuronal function and survival through compromised EAAT activity. A family of such diseases are those caused by expansion of CAG repeats in genes of the ataxin family, resulting in spinocerebellar ataxias (SCA). We investigated the contribution of BG to the pathogenesis of cerebellar neurodegeneration in a model of SCA1, which was induced by expression of a polyglutamine mutant of ataxin-1 (ATXN1[Q85]) in BG specifically. We compared the outcomes with a novel model where we triggered excitotoxicity by a chronic optogenetic activation of BG with channelrhodopsin-2 (ChR2). In both cases we detected evidence of reduced glutamate uptake manifested by prolongation of excitatory postsynaptic currents in Purkinje cells which is consistent with documented reduction of expression and/or function of EAAT1. In both models we detected astroglyosis and Purkinje cells atrophy. Finally, the same pattern was detected in a knock-in mouse which expresses a polyglutamine mutant ataxin-1 ATXN1[Q154] in a non-cell-selective manner. Our results suggest that ATXN1[Q85] and ChR2-induced insult targeted to BG closely mimics SCA1 pathology, where excessive glutamate signaling appears to be a common feature likely being an important contributor to cerebellar neurodegeneration.

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Belozor O. S. et al. Chronic optogenetic stimulation of Bergman glia leads to dysfunction of EAAT1 and Purkinje cell death, mimicking the events caused by expression of pathogenic ataxin-1 // Neurobiology of Disease. 2021. Vol. 154. p. 105340.
GOST all authors (up to 50) Copy
Belozor O. S., Mozhei O., Yakovleva D. A., Potapenko I. V., Shuvaev A. N., Smolnikova M., Salmin V. V., Salmina A. B., Hirai H., Teschemacher A. G., Kasparov S. Chronic optogenetic stimulation of Bergman glia leads to dysfunction of EAAT1 and Purkinje cell death, mimicking the events caused by expression of pathogenic ataxin-1 // Neurobiology of Disease. 2021. Vol. 154. p. 105340.
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RIS Copy
TY - JOUR
DO - 10.1016/j.nbd.2021.105340
UR - https://doi.org/10.1016%2Fj.nbd.2021.105340
TI - Chronic optogenetic stimulation of Bergman glia leads to dysfunction of EAAT1 and Purkinje cell death, mimicking the events caused by expression of pathogenic ataxin-1
T2 - Neurobiology of Disease
AU - Shuvaev, A. N.
AU - Belozor, Olga S
AU - Mozhei, Oleg
AU - Yakovleva, Dariya A
AU - Potapenko, Ilia V
AU - Smolnikova, Marina
AU - Salmin, Vladimir V
AU - Salmina, Alla B.
AU - Hirai, Hirokazu
AU - Teschemacher, Anja G.
AU - Kasparov, Sergey
PY - 2021
DA - 2021/07/01 00:00:00
PB - Elsevier
SP - 105340
VL - 154
SN - 0969-9961
SN - 1095-953X
ER -
BibTex
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BibTex Copy
@article{2021_Belozor
author = {A. N. Shuvaev and Olga S Belozor and Oleg Mozhei and Dariya A Yakovleva and Ilia V Potapenko and Marina Smolnikova and Vladimir V Salmin and Alla B. Salmina and Hirokazu Hirai and Anja G. Teschemacher and Sergey Kasparov},
title = {Chronic optogenetic stimulation of Bergman glia leads to dysfunction of EAAT1 and Purkinje cell death, mimicking the events caused by expression of pathogenic ataxin-1},
journal = {Neurobiology of Disease},
year = {2021},
volume = {154},
publisher = {Elsevier},
month = {jul},
url = {https://doi.org/10.1016%2Fj.nbd.2021.105340},
pages = {105340},
doi = {10.1016/j.nbd.2021.105340}
}
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