In:
PLOS Biology, Public Library of Science (PLoS), Vol. 19, No. 11 ( 2021-11-8), p. e3001350-
Abstract:
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 Ca 2+ permeability. Further biochemical and proximity ligation assay (PLA) studies defined the presence of GluA1/GluA2 (Ca 2+ impermeable) as well as GluA1/GluA4 (Ca 2+ 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.
Type of Medium:
Online Resource
ISSN:
1545-7885
DOI:
10.1371/journal.pbio.3001350
DOI:
10.1371/journal.pbio.3001350.g001
DOI:
10.1371/journal.pbio.3001350.g002
DOI:
10.1371/journal.pbio.3001350.g003
DOI:
10.1371/journal.pbio.3001350.g004
DOI:
10.1371/journal.pbio.3001350.g005
DOI:
10.1371/journal.pbio.3001350.g006
DOI:
10.1371/journal.pbio.3001350.s001
DOI:
10.1371/journal.pbio.3001350.s002
DOI:
10.1371/journal.pbio.3001350.s003
DOI:
10.1371/journal.pbio.3001350.s004
DOI:
10.1371/journal.pbio.3001350.s005
DOI:
10.1371/journal.pbio.3001350.s006
DOI:
10.1371/journal.pbio.3001350.s007
DOI:
10.1371/journal.pbio.3001350.s008
DOI:
10.1371/journal.pbio.3001350.s009
DOI:
10.1371/journal.pbio.3001350.s010
DOI:
10.1371/journal.pbio.3001350.s011
DOI:
10.1371/journal.pbio.3001350.s012
DOI:
10.1371/journal.pbio.3001350.s013
DOI:
10.1371/journal.pbio.3001350.s014
DOI:
10.1371/journal.pbio.3001350.s015
DOI:
10.1371/journal.pbio.3001350.s016
DOI:
10.1371/journal.pbio.3001350.r001
DOI:
10.1371/journal.pbio.3001350.r002
DOI:
10.1371/journal.pbio.3001350.r003
DOI:
10.1371/journal.pbio.3001350.r004
DOI:
10.1371/journal.pbio.3001350.r005
DOI:
10.1371/journal.pbio.3001350.r006
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2021
detail.hit.zdb_id:
2126773-X
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