{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T18:00:41Z","timestamp":1790186441020,"version":"4.1.0"},"reference-count":100,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,10,1]],"date-time":"2021-10-01T00:00:00Z","timestamp":1633046400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Health \u2013 Ricerca Corrente and 5 \u00d7 1000 (to FMS and FS)","award":["none"],"award-info":[{"award-number":["none"]}]},{"DOI":"10.13039\/100015962","name":"Fondazione Cassa di Risparmio di Lucca","doi-asserted-by":"publisher","award":["--"],"award-info":[{"award-number":["--"]}],"id":[{"id":"10.13039\/100015962","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>A serotonergic dysfunction has been largely postulated as the main cause of depression, mainly due to its effective response to drugs that increase the serotonergic tone, still currently the first therapeutic line in this mood disorder. However, other dysfunctional pathomechanisms are likely involved in the disorder, and this may in part explain why some individuals with depression are resistant to serotonergic therapies. Among these, emerging evidence suggests a role for the astrocytic inward rectifier potassium channel 4.1 (Kir4.1) as an important modulator of neuronal excitability and glutamate metabolism. To discuss the relationship between Kir4.1 dysfunction and depression, a systematic review was performed according to the PRISMA statement. Searches were conducted across PubMed, Scopus, and Web of Science by two independent reviewers. Twelve studies met the inclusion criteria, analyzing Kir4.1 relationships with depression, through in vitro, in vivo, and post-mortem investigations. Increasing, yet not conclusive, evidence suggests a potential pathogenic role for Kir4.1 upregulation in depression. However, the actual contribution in the diverse subtypes of the disorder and in the comorbid conditions, for example, the epilepsy-depression comorbidity, remain elusive. Further studies are needed to better define the clinical phenotype associated with Kir4.1 dysfunction in humans and the molecular mechanisms by which it contributes to depression and implications for future treatments.<\/jats:p>","DOI":"10.3390\/cells10102628","type":"journal-article","created":{"date-parts":[[2021,10,1]],"date-time":"2021-10-01T10:55:40Z","timestamp":1633085740000},"page":"2628","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Kir4.1 Dysfunction in the Pathophysiology of Depression: A Systematic Review"],"prefix":"10.3390","volume":"10","author":[{"given":"Stefania","family":"Della Vecchia","sequence":"first","affiliation":[{"name":"Department of Developmental Neuroscience, IRCCS Stella Maris Foundation, Calambrone, 56128 Pisa, Italy"},{"name":"Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0194-0702","authenticated-orcid":false,"given":"Maria","family":"Marchese","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, IRCCS Stella Maris Foundation, Via dei Giacinti 2, 56128 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1359-9062","authenticated-orcid":false,"given":"Filippo Maria","family":"Santorelli","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, IRCCS Stella Maris Foundation, Via dei Giacinti 2, 56128 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Sicca","sequence":"additional","affiliation":[{"name":"Department of Developmental Neuroscience, IRCCS Stella Maris Foundation, Calambrone, 56128 Pisa, Italy"},{"name":"Child Neuropsychiatric Unit, USL Centro Toscana, 59100 Prato, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1001\/jamapsychiatry.2017.4602","article-title":"Epidemiology of adult DSM-5 major depressive disorder and its specifiers in the United States","volume":"75","author":"Hasin","year":"2018","journal-title":"JAMA Psychiatry"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1016\/S0140-6736(11)60871-4","article-title":"Depression in adolescence","volume":"379","author":"Thapar","year":"2012","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"American Psychiatric Association (2013). 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