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Although B-Raf proto-oncogene (\n                    <jats:italic>BRAF<\/jats:italic>\n                    ) mutations are associated with cardio-facio-cutaneous (CFC) syndrome and Noonan syndrome, it remains unclear how these mutations impair cognition. Here, we investigated the underlying neural mechanisms using several mouse models harboring a gain-of-function BRAF mutation (K499E) discovered in RASopathy patients. We found expressing BRAF K499E (KE) in neural stem cells under the control of a Nestin-Cre promoter (Nestin;BRAF\n                    <jats:sup>KE\/+<\/jats:sup>\n                    ) induced hippocampal memory deficits, but expressing it in excitatory or inhibitory neurons did not. BRAF KE expression in neural stem cells led to aberrant reactive astrogliosis, increased astrocytic Ca\n                    <jats:sup>2+<\/jats:sup>\n                    fluctuations, and reduced hippocampal long-term depression (LTD) in mice. Consistently, 3D human cortical spheroids expressing BRAF KE also showed reactive astrogliosis. Astrocyte-specific adeno-associated virus\u2013BRAF KE (AAV-BRAF KE) delivery induced memory deficits and reactive astrogliosis and increased astrocytic Ca\n                    <jats:sup>2+<\/jats:sup>\n                    fluctuations. Notably, reducing extracellular signal-regulated kinase (ERK) activity in astrocytes rescued the memory deficits and altered astrocytic Ca\n                    <jats:sup>2+<\/jats:sup>\n                    activity of Nestin;BRAF\n                    <jats:sup>KE\/+<\/jats:sup>\n                    mice. Furthermore, reducing astrocyte Ca\n                    <jats:sup>2+<\/jats:sup>\n                    activity rescued the spatial memory impairments of BRAF KE\u2013expressing mice. Our results demonstrate that ERK hyperactivity contributes to astrocyte dysfunction associated with Ca\n                    <jats:sup>2+<\/jats:sup>\n                    dysregulation, leading to the memory deficits of\n                    <jats:italic>BRAF<\/jats:italic>\n                    -associated RASopathies.\n                  <\/jats:p>","DOI":"10.1172\/jci176631","type":"journal-article","created":{"date-parts":[[2025,2,18]],"date-time":"2025-02-18T12:01:04Z","timestamp":1739880064000},"source":"Crossref","is-referenced-by-count":9,"title":["Aberrant ERK signaling in astrocytes impairs learning and memory in RASopathy-associated BRAF mutant mouse models"],"prefix":"10.1172","volume":"135","author":[{"given":"Minkyung","family":"Kang","sequence":"first","affiliation":[{"name":"Department of Physiology, and"},{"name":"Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jihye","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Republic of Korea."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeongho","family":"Han","sequence":"additional","affiliation":[{"name":"Research Group of Neurovascular Unit, Korea Brain Research Institute, Daegu, Republic of Korea."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshiyuki","family":"Araki","sequence":"additional","affiliation":[{"name":"Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soo-Whee","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Integrated Biomedical and Life Science, and"},{"name":"BK21FOUR R&E Center for Learning Health Systems, Korea University, Seoul, Republic of Korea."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6147-5075","authenticated-orcid":true,"given":"Hyun-Hee","family":"Ryu","sequence":"additional","affiliation":[{"name":"Department of Physiology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min-Gyun","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Physiology, and"},{"name":"Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seoyeon","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Integrated Biomedical and Life Science, and"},{"name":"BK21FOUR R&E Center for Learning Health Systems, Korea University, Seoul, Republic of 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Korea."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kitae","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Physiology, and"},{"name":"Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pojeong","family":"Park","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, Seoul National University, Seoul, Republic of Korea."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ja Eun","family":"Choi","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, Seoul National University, Seoul, Republic of Korea."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dae Hee","family":"Han","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, Seoul National University, Seoul, Republic of Korea."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujin","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Integrated Biomedical and Life Science, and"},{"name":"BK21FOUR R&E Center for Learning Health Systems, Korea University, Seoul, Republic of Korea."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeongyeon","family":"Kim","sequence":"additional","affiliation":[{"name":"Emotion, Cognition and Behavior Research Group, Korea Brain Research Institute, Daegu, Republic of Korea."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3446-7288","authenticated-orcid":true,"given":"Sunghoe","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Physiology, and"},{"name":"Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bong-Kiun","family":"Kaang","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, Seoul National University, Seoul, Republic of Korea."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0407-7828","authenticated-orcid":true,"given":"Jung Min","family":"Ko","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Clinical Genetics, Seoul National University College of Medicine, Seoul, Republic of Korea."},{"name":"Rare Disease Center, Seoul National University Hospital, Seoul, Republic of Korea."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keun-Ah","family":"Cheon","sequence":"additional","affiliation":[{"name":"Department of Child and Adolescent Psychiatry, Severance Hospital, and"},{"name":"Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Yonsei University Health 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