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Despite the large use of antidepressants in current medical practice, neither their mechanisms of action nor the aetiology of MDD are completely understood. Experimental evidence supports the involvement of Parvalbumin-positive GABAergic neurons (PV-neurons) in the pathogenesis of MDD. DLX5 and DLX6 (DLX5\/6) encode two homeodomain transcription factors involved in cortical GABAergic differentiation and function. In the mouse, the level of expression of these genes is correlated with the cortical density of PV-neurons and with anxiety-like behaviours. The same genomic region generates the lncRNA DLX6-AS1, which, in humans, participates in the GABAergic regulatory module downregulated in schizophrenia and ASD. Here, we show that the expression levels of Dlx5\/6 in the adult mouse brain are correlated with the immobility time in the forced swim test, which is used to measure depressive-like behaviours. We show that the administration of the antidepressant fluoxetine (Flx) to normal mice induces, within 24 h, a rapid and stable reduction in Dlx5, Dlx6 and Dlx6-AS1 expression in the cerebral cortex through the activation of the TrkB-CREB pathway. Experimental Dlx5 overexpression counteracts the antidepressant effects induced by Flx treatment. Our findings show that one of the short-term effects of Flx administration is the reduction in Dlx5\/6 expression in GABAergic neurons, which, in turn, has direct consequences on PV expression and on behavioural profiles. Variants in the DLX5\/6 regulatory network could be implicated in the predisposition to depression and in the variability of patients\u2019 response to antidepressant treatment.<\/jats:p>","DOI":"10.3390\/cells13151262","type":"journal-article","created":{"date-parts":[[2024,7,26]],"date-time":"2024-07-26T13:04:59Z","timestamp":1721999099000},"page":"1262","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["The Antidepressant Action of Fluoxetine Involves the Inhibition of Dlx5\/6 in Cortical GABAergic Neurons through a TrkB-Dependent Pathway"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6728-0292","authenticated-orcid":false,"given":"Rym","family":"Aouci","sequence":"first","affiliation":[{"name":"Molecular Physiology and Adaption, UMR7221 CNRS, Museum National d\u2019Histoire Naturelle, 75005 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasia","family":"Fontaine","sequence":"additional","affiliation":[{"name":"Molecular Physiology and Adaption, UMR7221 CNRS, Museum National d\u2019Histoire Naturelle, 75005 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Am\u00efn","family":"Vion","sequence":"additional","affiliation":[{"name":"Molecular Physiology and Adaption, UMR7221 CNRS, Museum National d\u2019Histoire Naturelle, 75005 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lou","family":"Belz","sequence":"additional","affiliation":[{"name":"Molecular Physiology and Adaption, UMR7221 CNRS, Museum National d\u2019Histoire Naturelle, 75005 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7041-6787","authenticated-orcid":false,"given":"Giovanni","family":"Levi","sequence":"additional","affiliation":[{"name":"Molecular Physiology and Adaption, UMR7221 CNRS, Museum National d\u2019Histoire Naturelle, 75005 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3791-7459","authenticated-orcid":false,"given":"Nicolas","family":"Narboux-N\u00eame","sequence":"additional","affiliation":[{"name":"Molecular Physiology and Adaption, UMR7221 CNRS, Museum National d\u2019Histoire Naturelle, 75005 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/S2215-0366(17)30015-9","article-title":"How do antidepressants work? 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