{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T12:18:04Z","timestamp":1789906684611,"version":"4.0.1"},"reference-count":77,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2022,10,4]],"date-time":"2022-10-04T00:00:00Z","timestamp":1664841600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003359","name":"European Regional Development Funds; Generalitat Valenciana","doi-asserted-by":"publisher","award":["PROMETEOII\/2018\/051"],"award-info":[{"award-number":["PROMETEOII\/2018\/051"]}],"id":[{"id":"10.13039\/501100003359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003359","name":"European Regional Development Funds; Generalitat Valenciana","doi-asserted-by":"publisher","award":["SAF2017-82917-R"],"award-info":[{"award-number":["SAF2017-82917-R"]}],"id":[{"id":"10.13039\/501100003359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003359","name":"European Regional Development Funds; Generalitat Valenciana","doi-asserted-by":"publisher","award":["PID2020-113388RB-I00"],"award-info":[{"award-number":["PID2020-113388RB-I00"]}],"id":[{"id":"10.13039\/501100003359","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ministerio de Ciencia e Innovacion","award":["PROMETEOII\/2018\/051"],"award-info":[{"award-number":["PROMETEOII\/2018\/051"]}]},{"name":"Ministerio de Ciencia e Innovacion","award":["SAF2017-82917-R"],"award-info":[{"award-number":["SAF2017-82917-R"]}]},{"name":"Ministerio de Ciencia e Innovacion","award":["PID2020-113388RB-I00"],"award-info":[{"award-number":["PID2020-113388RB-I00"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Background: Hyperammonemia is a main contributor to minimal hepatic encephalopathy (MHE) in cirrhotic patients. Hyperammonemic rats reproduce the motor incoordination of MHE patients, which is due to enhanced GABAergic neurotransmission in the cerebellum as a consequence of neuroinflammation. In hyperammonemic rats, neuroinflammation increases BDNF by activating the TNFR1\u2013S1PR2\u2013CCR2 pathway. (1) Identify mechanisms enhancing GABAergic neurotransmission in hyperammonemia; (2) assess the role of enhanced activation of TrkB; and (3) assess the role of the TNFR1\u2013S1PR2\u2013CCR2\u2013BDNF pathway. In the cerebellum of hyperammonemic rats, increased BDNF levels enhance TrkB activation in Purkinje neurons, leading to increased GAD65, GAD67 and GABA levels. Enhanced TrkB activation also increases the membrane expression of the \u03b32, \u03b12 and \u03b23 subunits of GABAA receptors and of KCC2. Moreover, enhanced TrkB activation in activated astrocytes increases the membrane expression of GAT3 and NKCC1. These changes are reversed by blocking TrkB or the TNFR1\u2013SP1PR2\u2013CCL2\u2013CCR2\u2013BDNF\u2013TrkB pathway. Hyperammonemia-induced neuroinflammation increases BDNF and TrkB activation, leading to increased synthesis and extracellular GABA, and the amount of GABAA receptors in the membrane and chloride gradient. These factors enhance GABAergic neurotransmission in the cerebellum. Blocking TrkB or the TNFR1\u2013SP1PR2\u2013CCL2\u2013CCR2\u2013BDNF\u2013TrkB pathway would improve motor function in patients with hepatic encephalopathy and likely with other pathologies associated with neuroinflammation.<\/jats:p>","DOI":"10.3390\/ijms231911770","type":"journal-article","created":{"date-parts":[[2022,10,8]],"date-time":"2022-10-08T23:39:31Z","timestamp":1665272371000},"page":"11770","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Enhanced BDNF and TrkB Activation Enhance GABA Neurotransmission in Cerebellum in Hyperammonemia"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6769-5888","authenticated-orcid":false,"given":"Yaiza M.","family":"Arenas","sequence":"first","affiliation":[{"name":"Laboratory of Neurobiology, Centro Investigaci\u00f3n Pr\u00edncipe Felipe, 46012 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar","family":"Mart\u00ednez-Garc\u00eda","sequence":"additional","affiliation":[{"name":"Laboratory of Neurobiology, Centro Investigaci\u00f3n Pr\u00edncipe Felipe, 46012 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5565-5907","authenticated-orcid":false,"given":"Marta","family":"Llansola","sequence":"additional","affiliation":[{"name":"Laboratory of Neurobiology, Centro Investigaci\u00f3n Pr\u00edncipe Felipe, 46012 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3145-9538","authenticated-orcid":false,"given":"Vicente","family":"Felipo","sequence":"additional","affiliation":[{"name":"Laboratory of Neurobiology, Centro Investigaci\u00f3n Pr\u00edncipe Felipe, 46012 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1016\/S0168-8278(00)80243-3","article-title":"Screening of subclinical hepatic encephalopathy","volume":"32","author":"Groeneweg","year":"2000","journal-title":"J. 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