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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\u2013derived neurotrophic factor receptor alpha 1 (GFR\u03b11) is required in adult mHb neurons for synaptic stability and function. mHb neurons express some of the highest levels of GFR\u03b11 in the mouse brain, and acute ablation of GFR\u03b11 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 GFR\u03b11 revealed impaired circuit connectivity, reduced AMPA receptor postsynaptic currents, and abnormally low rectification index (R.I.) of AMPARs, suggesting reduced Ca\n                    <jats:sup>2+<\/jats:sup>\n                    permeability. Further biochemical and proximity ligation assay (PLA) studies defined the presence of GluA1\/GluA2 (Ca\n                    <jats:sup>2+<\/jats:sup>\n                    impermeable) as well as GluA1\/GluA4 (Ca\n                    <jats:sup>2+<\/jats:sup>\n                    permeable) AMPAR complexes in mHb neurons, as well as clear differences in the levels and association of AMPAR subunits with mHb neurons lacking GFR\u03b11. Finally, acute loss of GFR\u03b11 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 GFR\u03b11 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.\n                  <\/jats:p>","DOI":"10.1371\/journal.pbio.3001350","type":"journal-article","created":{"date-parts":[[2021,11,8]],"date-time":"2021-11-08T13:40:43Z","timestamp":1636378843000},"page":"e3001350","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":14,"title":["Adult medial habenula neurons require GDNF receptor GFR\u03b11 for synaptic stability and function"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1381-871X","authenticated-orcid":true,"given":"Diana","family":"Fern\u00e1ndez-Su\u00e1rez","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8437-7061","authenticated-orcid":true,"given":"Favio A.","family":"Krapacher","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katarzyna","family":"Pietrajtis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3291-6032","authenticated-orcid":true,"given":"Annika","family":"Andersson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lilian","family":"Kisiswa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0889-709X","authenticated-orcid":true,"given":"Alvaro","family":"Carrier-Ruiz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8928-0154","authenticated-orcid":true,"given":"Marco A.","family":"Diana","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlos F.","family":"Ib\u00e1\u00f1ez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,11,8]]},"reference":[{"key":"pbio.3001350.ref001","doi-asserted-by":"crossref","first-page":"138","DOI":"10.3389\/fnins.2011.00138","article-title":"Phylogeny and ontogeny of the habenular structure","volume":"5","author":"H Aizawa","year":"2011","journal-title":"Front Neurosci"},{"issue":"11","key":"pbio.3001350.ref002","doi-asserted-by":"crossref","first-page":"1354","DOI":"10.1038\/nn.2654","article-title":"The habenula is crucial for experience-dependent modification of fear responses in zebrafish","volume":"13","author":"M Agetsuma","year":"2010","journal-title":"Nat Neurosci"},{"issue":"5","key":"pbio.3001350.ref003","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1016\/j.neubiorev.2007.01.004","article-title":"A conductor hidden in the orchestra? 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