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GluD1, linked to schizophrenia, controls the burst firing of dopamine neurons

Human mutations of the GRID1 gene encoding the orphan delta1 glutamate receptor-channel (GluD1) are associated with schizophrenia but the explicit role of GluD1 in brain circuits is unknown. Based on the known function of its paralog GluD2 in cerebellum, we searched for a role of GluD1 in slow gluta...

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Autores principales: Benamer, N, Marti, F, Lujan, R, Hepp, R, Aubier, T G, Dupin, A A M, Frébourg, G, Pons, S, Maskos, U, Faure, P, Hay, Y A, Lambolez, B, Tricoire, L
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5822454/
https://www.ncbi.nlm.nih.gov/pubmed/28696429
http://dx.doi.org/10.1038/mp.2017.137
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author Benamer, N
Marti, F
Lujan, R
Hepp, R
Aubier, T G
Dupin, A A M
Frébourg, G
Pons, S
Maskos, U
Faure, P
Hay, Y A
Lambolez, B
Tricoire, L
author_facet Benamer, N
Marti, F
Lujan, R
Hepp, R
Aubier, T G
Dupin, A A M
Frébourg, G
Pons, S
Maskos, U
Faure, P
Hay, Y A
Lambolez, B
Tricoire, L
author_sort Benamer, N
collection PubMed
description Human mutations of the GRID1 gene encoding the orphan delta1 glutamate receptor-channel (GluD1) are associated with schizophrenia but the explicit role of GluD1 in brain circuits is unknown. Based on the known function of its paralog GluD2 in cerebellum, we searched for a role of GluD1 in slow glutamatergic transmission mediated by metabotropic receptor mGlu1 in midbrain dopamine neurons, whose dysfunction is a hallmark of schizophrenia. We found that an mGlu1 agonist elicits a slow depolarizing current in HEK cells co-expressing mGlu1 and GluD1, but not in cells expressing mGlu1 or GluD1 alone. This current is abolished by additional co-expression of a dominant-negative GluD1 dead pore mutant. We then characterized mGlu1-dependent currents in dopamine neurons from midbrain slices. Both the agonist-evoked and the slow postsynaptic currents are abolished by expression of the dominant-negative GluD1 mutant, pointing to the involvement of native GluD1 channels in these currents. Likewise, both mGlu1-dependent currents are suppressed in GRID1 knockout mice, which reportedly display endophenotypes relevant for schizophrenia. It is known that mGlu1 activation triggers the transition from tonic to burst firing of dopamine neurons, which signals salient stimuli and encodes reward prediction. In vivo recordings of dopamine neurons showed that their spontaneous burst firing is abolished in GRID1 knockout mice or upon targeted expression of the dominant-negative GluD1 mutant in wild-type mice. Our results de-orphanize GluD1, unravel its key role in slow glutamatergic transmission and provide insights into how GRID1 gene alterations can lead to dopaminergic dysfunctions in schizophrenia.
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spelling pubmed-58224542018-02-23 GluD1, linked to schizophrenia, controls the burst firing of dopamine neurons Benamer, N Marti, F Lujan, R Hepp, R Aubier, T G Dupin, A A M Frébourg, G Pons, S Maskos, U Faure, P Hay, Y A Lambolez, B Tricoire, L Mol Psychiatry Original Article Human mutations of the GRID1 gene encoding the orphan delta1 glutamate receptor-channel (GluD1) are associated with schizophrenia but the explicit role of GluD1 in brain circuits is unknown. Based on the known function of its paralog GluD2 in cerebellum, we searched for a role of GluD1 in slow glutamatergic transmission mediated by metabotropic receptor mGlu1 in midbrain dopamine neurons, whose dysfunction is a hallmark of schizophrenia. We found that an mGlu1 agonist elicits a slow depolarizing current in HEK cells co-expressing mGlu1 and GluD1, but not in cells expressing mGlu1 or GluD1 alone. This current is abolished by additional co-expression of a dominant-negative GluD1 dead pore mutant. We then characterized mGlu1-dependent currents in dopamine neurons from midbrain slices. Both the agonist-evoked and the slow postsynaptic currents are abolished by expression of the dominant-negative GluD1 mutant, pointing to the involvement of native GluD1 channels in these currents. Likewise, both mGlu1-dependent currents are suppressed in GRID1 knockout mice, which reportedly display endophenotypes relevant for schizophrenia. It is known that mGlu1 activation triggers the transition from tonic to burst firing of dopamine neurons, which signals salient stimuli and encodes reward prediction. In vivo recordings of dopamine neurons showed that their spontaneous burst firing is abolished in GRID1 knockout mice or upon targeted expression of the dominant-negative GluD1 mutant in wild-type mice. Our results de-orphanize GluD1, unravel its key role in slow glutamatergic transmission and provide insights into how GRID1 gene alterations can lead to dopaminergic dysfunctions in schizophrenia. Nature Publishing Group 2018 2017-07-11 /pmc/articles/PMC5822454/ /pubmed/28696429 http://dx.doi.org/10.1038/mp.2017.137 Text en Copyright © 2018 The Author(s) http://creativecommons.org/licenses/by-nc-sa/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/
spellingShingle Original Article
Benamer, N
Marti, F
Lujan, R
Hepp, R
Aubier, T G
Dupin, A A M
Frébourg, G
Pons, S
Maskos, U
Faure, P
Hay, Y A
Lambolez, B
Tricoire, L
GluD1, linked to schizophrenia, controls the burst firing of dopamine neurons
title GluD1, linked to schizophrenia, controls the burst firing of dopamine neurons
title_full GluD1, linked to schizophrenia, controls the burst firing of dopamine neurons
title_fullStr GluD1, linked to schizophrenia, controls the burst firing of dopamine neurons
title_full_unstemmed GluD1, linked to schizophrenia, controls the burst firing of dopamine neurons
title_short GluD1, linked to schizophrenia, controls the burst firing of dopamine neurons
title_sort glud1, linked to schizophrenia, controls the burst firing of dopamine neurons
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5822454/
https://www.ncbi.nlm.nih.gov/pubmed/28696429
http://dx.doi.org/10.1038/mp.2017.137
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