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Although PRDX6 can modulate several signaling cascades involving cognitive functions, its physiological role in spatial memory has not been investigated yet. This study aims to explore the function of the <jats:italic>Prdx6<\/jats:italic> gene in spatial memory formation and synaptic plasticity. We first tested <jats:italic>Prdx6<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice on a Morris water maze task and found that their memory performance was defective, along with reduced long-term potentiation (LTP) in CA3-CA1 hippocampal synapses recorded from hippocampal sections of home-caged mice. Surprisingly, after the probe test, these knockout mice exhibited elevated hippocampal LTP, higher phosphorylated ERK1\/2 level, and decreased reactive astrocyte markers. We further reduced ERK1\/2 phosphorylation by administering MEK inhibitor, U0126, into <jats:italic>Prdx6<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice before the probe test, which\u00a0reversed  their spatial memory deficit. This study is the first one to report the role of PRDX6 in spatial memory and synaptic plasticity. Our results revealed that PRDX6 is necessary for maintaining spatial memory by modulating ERK1\/2 phosphorylation and astrocyte activation.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Graphic Abstract<\/jats:title>\n                \n              <\/jats:sec>","DOI":"10.1186\/s13041-021-00779-6","type":"journal-article","created":{"date-parts":[[2021,4,19]],"date-time":"2021-04-19T18:14:58Z","timestamp":1618856098000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Lack of the peroxiredoxin 6 gene causes impaired spatial memory and abnormal synaptic plasticity"],"prefix":"10.1186","volume":"14","author":[{"given":"Sarayut","family":"Phasuk","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sureka","family":"Jasmin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tanita","family":"Pairojana","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hsueh-Kai","family":"Chang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kai-Chi","family":"Liang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2795-2461","authenticated-orcid":false,"given":"Ingrid Y.","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,4,19]]},"reference":[{"issue":"4","key":"779_CR1","doi-asserted-by":"publisher","first-page":"478","DOI":"10.1007\/s11065-009-9120-3","volume":"19","author":"SD Moffat","year":"2009","unstructured":"Moffat SD. 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