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We investigated its role in contextual fear conditioning and extinction of conditioned fear using <jats:italic>Trpm2-<\/jats:italic>deficient (<jats:italic>Trpm2<\/jats:italic>\n            <jats:sup>\n              <jats:italic>\u2212\/\u2212<\/jats:italic>\n            <\/jats:sup>) mice. <jats:italic>Trpm2<\/jats:italic>\n            <jats:sup>\n              <jats:italic>\u2212\/\u2212<\/jats:italic>\n            <\/jats:sup> mice exhibited reduced acquisition of contextual fear memory during conditioning but had an intact freezing response to conditioning context 24\u00a0h after conditioning. They also showed a reduced freezing response to extinction training, indicating facilitated extinction. Consistent with this, infusion of flufenamic acid (FFA), a TRPM2 antagonist, into the dentate gyrus (DG) of the hippocampus in fear-conditioned mice facilitated extinction of contextual fear. The enhanced extinction in <jats:italic>Trpm2<\/jats:italic>\n            <jats:sup>\n              <jats:italic>\u2212\/\u2212<\/jats:italic>\n            <\/jats:sup> and FFA-treated mice was associated with down-regulation of immediate-early genes (IEGs) including <jats:italic>Npas4, c-Fos, Arc<\/jats:italic> and <jats:italic>Egr1<\/jats:italic> in the hippocampus after extinction training. Our results indicate that TRPM2 plays a positive role in retention of contextual fear memory by modulating neuronal activity in the hippocampus, and suggest that TRPM2 activity could potentially be targeted to strengthen extinction-based exposure therapies for post-traumatic stress disorder (PTSD).<\/jats:p>","DOI":"10.1186\/s13041-025-01181-2","type":"journal-article","created":{"date-parts":[[2025,2,28]],"date-time":"2025-02-28T12:41:52Z","timestamp":1740746512000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Extinction of contextual fear memory is facilitated in TRPM2 knockout mice"],"prefix":"10.1186","volume":"18","author":[{"given":"Seung Yeon","family":"Ko","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Do Gyeong","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huiju","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sung Jun","family":"Jung","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyeon","family":"Son","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,2,27]]},"reference":[{"issue":"5","key":"1181_CR1","doi-asserted-by":"publisher","first-page":"397","DOI":"10.3390\/life11050397","volume":"11","author":"A Szollosi","year":"2021","unstructured":"Szollosi A. 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