Adult medial habenula neurons require GDNF receptor GFRα1 for synaptic stability and function

The medial habenula (mHb) is an understudied small brain nucleus linking forebrain and midbrain structures controlling anxiety and fear behaviors. The mechanisms that maintain the structural and functional integrity of mHb neurons and their synapses remain unknown. Using spatiotemporally controlled...

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Autores principales:	Diana Fernández-Suárez, Favio A. Krapacher, Katarzyna Pietrajtis, Annika Andersson, Lilian Kisiswa, Alvaro Carrier-Ruiz, Marco A. Diana, Carlos F. Ibáñez
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/668b502142bc4c6187e6c5ac87765bdd
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spelling	oai:doaj.org-article:668b502142bc4c6187e6c5ac87765bdd2021-11-25T05:33:35ZAdult medial habenula neurons require GDNF receptor GFRα1 for synaptic stability and function1544-91731545-7885https://doaj.org/article/668b502142bc4c6187e6c5ac87765bdd2021-11-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8601618/?tool=EBIhttps://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885The medial habenula (mHb) is an understudied small brain nucleus linking forebrain and midbrain structures controlling anxiety and fear behaviors. The mechanisms that maintain the structural and functional integrity of mHb neurons and their synapses remain unknown. Using spatiotemporally controlled Cre-mediated recombination in adult mice, we found that the glial cell–derived neurotrophic factor receptor alpha 1 (GFRα1) is required in adult mHb neurons for synaptic stability and function. mHb neurons express some of the highest levels of GFRα1 in the mouse brain, and acute ablation of GFRα1 results in loss of septohabenular and habenulointerpeduncular glutamatergic synapses, with the remaining synapses displaying reduced numbers of presynaptic vesicles. Chemo- and optogenetic studies in mice lacking GFRα1 revealed impaired circuit connectivity, reduced AMPA receptor postsynaptic currents, and abnormally low rectification index (R.I.) of AMPARs, suggesting reduced Ca2+ permeability. Further biochemical and proximity ligation assay (PLA) studies defined the presence of GluA1/GluA2 (Ca2+ impermeable) as well as GluA1/GluA4 (Ca2+ permeable) AMPAR complexes in mHb neurons, as well as clear differences in the levels and association of AMPAR subunits with mHb neurons lacking GFRα1. Finally, acute loss of GFRα1 in adult mHb neurons reduced anxiety-like behavior and potentiated context-based fear responses, phenocopying the effects of lesions to septal projections to the mHb. These results uncover an unexpected function for GFRα1 in the maintenance and function of adult glutamatergic synapses and reveal a potential new mechanism for regulating synaptic plasticity in the septohabenulointerpeduncular pathway and attuning of anxiety and fear behaviors. The GPI-anchored protein GFRα1 is highly expressed in the habenula, but its role in the adult nervous system remains unknown. This study explores the role of GFRα1 in habenular neuron function, revealing that it regulates the maintenance of adult synapses in the septohabenular pathway, AMPA-mediated glutamatergic signaling, and fear and anxiety behaviors.Diana Fernández-SuárezFavio A. KrapacherKatarzyna PietrajtisAnnika AnderssonLilian KisiswaAlvaro Carrier-RuizMarco A. DianaCarlos F. IbáñezPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 19, Iss 11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Diana Fernández-Suárez Favio A. Krapacher Katarzyna Pietrajtis Annika Andersson Lilian Kisiswa Alvaro Carrier-Ruiz Marco A. Diana Carlos F. Ibáñez Adult medial habenula neurons require GDNF receptor GFRα1 for synaptic stability and function
description	The medial habenula (mHb) is an understudied small brain nucleus linking forebrain and midbrain structures controlling anxiety and fear behaviors. The mechanisms that maintain the structural and functional integrity of mHb neurons and their synapses remain unknown. Using spatiotemporally controlled Cre-mediated recombination in adult mice, we found that the glial cell–derived neurotrophic factor receptor alpha 1 (GFRα1) is required in adult mHb neurons for synaptic stability and function. mHb neurons express some of the highest levels of GFRα1 in the mouse brain, and acute ablation of GFRα1 results in loss of septohabenular and habenulointerpeduncular glutamatergic synapses, with the remaining synapses displaying reduced numbers of presynaptic vesicles. Chemo- and optogenetic studies in mice lacking GFRα1 revealed impaired circuit connectivity, reduced AMPA receptor postsynaptic currents, and abnormally low rectification index (R.I.) of AMPARs, suggesting reduced Ca2+ permeability. Further biochemical and proximity ligation assay (PLA) studies defined the presence of GluA1/GluA2 (Ca2+ impermeable) as well as GluA1/GluA4 (Ca2+ permeable) AMPAR complexes in mHb neurons, as well as clear differences in the levels and association of AMPAR subunits with mHb neurons lacking GFRα1. Finally, acute loss of GFRα1 in adult mHb neurons reduced anxiety-like behavior and potentiated context-based fear responses, phenocopying the effects of lesions to septal projections to the mHb. These results uncover an unexpected function for GFRα1 in the maintenance and function of adult glutamatergic synapses and reveal a potential new mechanism for regulating synaptic plasticity in the septohabenulointerpeduncular pathway and attuning of anxiety and fear behaviors. The GPI-anchored protein GFRα1 is highly expressed in the habenula, but its role in the adult nervous system remains unknown. This study explores the role of GFRα1 in habenular neuron function, revealing that it regulates the maintenance of adult synapses in the septohabenular pathway, AMPA-mediated glutamatergic signaling, and fear and anxiety behaviors.
format	article
author	Diana Fernández-Suárez Favio A. Krapacher Katarzyna Pietrajtis Annika Andersson Lilian Kisiswa Alvaro Carrier-Ruiz Marco A. Diana Carlos F. Ibáñez
author_facet	Diana Fernández-Suárez Favio A. Krapacher Katarzyna Pietrajtis Annika Andersson Lilian Kisiswa Alvaro Carrier-Ruiz Marco A. Diana Carlos F. Ibáñez
author_sort	Diana Fernández-Suárez
title	Adult medial habenula neurons require GDNF receptor GFRα1 for synaptic stability and function
title_short	Adult medial habenula neurons require GDNF receptor GFRα1 for synaptic stability and function
title_full	Adult medial habenula neurons require GDNF receptor GFRα1 for synaptic stability and function
title_fullStr	Adult medial habenula neurons require GDNF receptor GFRα1 for synaptic stability and function
title_full_unstemmed	Adult medial habenula neurons require GDNF receptor GFRα1 for synaptic stability and function
title_sort	adult medial habenula neurons require gdnf receptor gfrα1 for synaptic stability and function
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/668b502142bc4c6187e6c5ac87765bdd
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Adult medial habenula neurons require GDNF receptor GFRα1 for synaptic stability and function

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