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
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...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-07-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996121000899 |
| _version_ | 1818720499187843072 |
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| author | Anton N. Shuvaev Olga S. Belozor Oleg Mozhei Dariya A. Yakovleva Ilya V. Potapenko Andrey N. Shuvaev Marina V. Smolnikova Vladimir V. Salmin Alla B. Salmina Hirokazu Hirai Anja G. Teschemacher Sergey Kasparov |
| author_facet | Anton N. Shuvaev Olga S. Belozor Oleg Mozhei Dariya A. Yakovleva Ilya V. Potapenko Andrey N. Shuvaev Marina V. Smolnikova Vladimir V. Salmin Alla B. Salmina Hirokazu Hirai Anja G. Teschemacher Sergey Kasparov |
| author_sort | Anton N. Shuvaev |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-17T20:23:48Z |
| format | Article |
| id | doaj.art-42b772dd45154454a13f5eaf63bcdd32 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-17T20:23:48Z |
| publishDate | 2021-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-42b772dd45154454a13f5eaf63bcdd322022-12-21T21:33:51ZengElsevierNeurobiology of Disease1095-953X2021-07-01154105340Chronic optogenetic stimulation of Bergman glia leads to dysfunction of EAAT1 and Purkinje cell death, mimicking the events caused by expression of pathogenic ataxin-1Anton N. Shuvaev0Olga S. Belozor1Oleg Mozhei2Dariya A. Yakovleva3Ilya V. Potapenko4Andrey N. Shuvaev5Marina V. Smolnikova6Vladimir V. Salmin7Alla B. Salmina8Hirokazu Hirai9Anja G. Teschemacher10Sergey Kasparov11Krasnoyarsk State Medical University named after Prof. V.F. Voino-Yasenetsky, Research Institute of Molecular Medicine and Pathobiochemistry, Partizan Zheleznyak st. 1, 660022 Krasnoyarsk, Russia; Corresponding author.Krasnoyarsk State Medical University named after Prof. V.F. Voino-Yasenetsky, Department of Biological Chemistry, Medical Pharmaceutical and Toxicological Chemistry, Partizan Zheleznyak st., 1, 660022 Krasnoyarsk, RussiaInstitute of Living Systems, Immanuel Kant Baltic Federal University, Universitetskaya st., 2, 236041 Kaliningrad, RussiaSiberian Federal University, Svobodny pr., 79, 660041 Krasnoyarsk, RussiaKrasnoyarsk State Medical University named after Prof. V.F. Voino-Yasenetsky, Research Institute of Molecular Medicine and Pathobiochemistry, Partizan Zheleznyak st. 1, 660022 Krasnoyarsk, RussiaSiberian Federal University, Svobodny pr., 79, 660041 Krasnoyarsk, RussiaKrasnoyarsk State Medical University named after Prof. V.F. Voino-Yasenetsky, Research Institute of Molecular Medicine and Pathobiochemistry, Partizan Zheleznyak st. 1, 660022 Krasnoyarsk, Russia; Federal Research Center “Krasnoyarsk Science Center” of the Siberian Branch of the Russian Academy of Sciences, Scientific Research Institute of Medical Problems of the North, Partizan Zheleznyak st., 3G, 660022 Krasnoyarsk, RussiaKrasnoyarsk State Medical University named after Prof. V.F. Voino-Yasenetsky, Department of Medical and Biological Physics, Partizan Zheleznyak st. 1, 660022 Krasnoyarsk, RussiaKrasnoyarsk State Medical University named after Prof. V.F. Voino-Yasenetsky, Research Institute of Molecular Medicine and Pathobiochemistry, Partizan Zheleznyak st. 1, 660022 Krasnoyarsk, Russia; Krasnoyarsk State Medical University named after Prof. V.F. Voino-Yasenetsky, Department of Biological Chemistry, Medical Pharmaceutical and Toxicological Chemistry, Partizan Zheleznyak st., 1, 660022 Krasnoyarsk, Russia; Laboratory of Experimental Brain Cytology, Division of Brain Sciences, Research Center of Neurology, Moscow 125367, RussiaDepartment of Neurophysiology & Neural Repair, Gunma University Graduate School of Medicine, Maebashi, JapanDepartment of Physiology, Pharmacology, and Neuroscience, University of Bristol, Bristol, United KingdomInstitute of Living Systems, Immanuel Kant Baltic Federal University, Universitetskaya st., 2, 236041 Kaliningrad, Russia; Department of Physiology, Pharmacology, and Neuroscience, University of Bristol, Bristol, United KingdomBergmann 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.http://www.sciencedirect.com/science/article/pii/S0969996121000899Bergmann gliaExcitatory amino acid transporter type 1Spinocerebellar ataxia type 1CerebellumPurkinje cell |
| spellingShingle | Anton N. Shuvaev Olga S. Belozor Oleg Mozhei Dariya A. Yakovleva Ilya V. Potapenko Andrey N. Shuvaev Marina V. Smolnikova Vladimir V. Salmin Alla B. Salmina Hirokazu Hirai Anja G. Teschemacher Sergey Kasparov 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 Bergmann glia Excitatory amino acid transporter type 1 Spinocerebellar ataxia type 1 Cerebellum Purkinje cell |
| 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | Bergmann glia Excitatory amino acid transporter type 1 Spinocerebellar ataxia type 1 Cerebellum Purkinje cell |
| url | http://www.sciencedirect.com/science/article/pii/S0969996121000899 |
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