Aberrant ERK signaling in astrocytes impairs learning and memory in RASopathy-associated BRAF mutant mouse models
DC Field | Value | Language |
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dc.contributor.author | Kang, Minkyung | - |
dc.contributor.author | Choi, Jihye | - |
dc.contributor.author | Han, Jeongho | - |
dc.contributor.author | Araki, Toshiyuki | - |
dc.contributor.author | Kim, Soo-Whee | - |
dc.contributor.author | Ryu, Hyun-Hee | - |
dc.contributor.author | Kim, Min-Gyun | - |
dc.contributor.author | Kim, Seoyeon | - |
dc.contributor.author | Jang, Hanbyul | - |
dc.contributor.author | Kim, Sun Yong | - |
dc.contributor.author | Hwang, Kyoung-Doo | - |
dc.contributor.author | Kim, Soobin | - |
dc.contributor.author | Yoo, Myeongjong | - |
dc.contributor.author | Lee, Jaegeon | - |
dc.contributor.author | Kim, Kitae | - |
dc.contributor.author | Park, Pojeong | - |
dc.contributor.author | Choi, Ja Eun | - |
dc.contributor.author | Han, Dae Hee | - |
dc.contributor.author | Kim, Yujin | - |
dc.contributor.author | Kim, Jeongyeon | - |
dc.contributor.author | Chang, Sunghoe | - |
dc.contributor.author | Kaang, Bong-Kiun | - |
dc.contributor.author | Ko, Jung Min | - |
dc.contributor.author | Cheon, Keun-Ah | - |
dc.contributor.author | An, Joon-Yong | - |
dc.contributor.author | Kim, Sang Jeong | - |
dc.contributor.author | Park, Hyungju | - |
dc.contributor.author | Neel, Benjamin G. | - |
dc.contributor.author | Kim, Chul Hoon | - |
dc.contributor.author | Lee, Yong-Seok | - |
dc.date.accessioned | 2025-03-04T07:30:16Z | - |
dc.date.available | 2025-03-04T07:30:16Z | - |
dc.date.issued | 2025-02 | - |
dc.identifier.issn | 0021-9738 | - |
dc.identifier.issn | 1558-8238 | - |
dc.identifier.uri | http://scholarworks.bwise.kr/kbri/handle/2023.sw.kbri/1246 | - |
dc.description.abstract | RAS/MAPK pathway mutations often induce RASopathies with overlapping features, such as craniofacial dysmorphology, cardiovascular defects, dermatologic abnormalities, and intellectual disabilities. Although BRAF gene 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;BRAFKE/+) 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 Ca2+ fluctuations, and reduced hippocampal long-term depression (LTD) in mice. Consistently, 3D human cortical spheroids expressing BRAF KE also showed reactive astrogliosis. Astrocyte-specific AAV-BRAF KE delivery induced memory deficits, reactive astrogliosis, and increased astrocytic Ca2+ fluctuations. Notably, reducing ERK activity in astrocytes rescued the memory deficits and altered astrocytic Ca2+ activity of Nestin;BRAFKE/+ mice. Furthermore, reducing astrocyte Ca2+ activity rescued the spatial memory impairments of BRAF KE-expressing mice. Our results demonstrate that ERK hyperactivity contributes to astrocyte dysfunction associated with Ca2+ dysregulation, leading to the memory deficits of BRAF-associated RASopathies. | - |
dc.language | 영어 | - |
dc.language.iso | ENG | - |
dc.publisher | American Society for Clinical Investigation | - |
dc.title | Aberrant ERK signaling in astrocytes impairs learning and memory in RASopathy-associated BRAF mutant mouse models | - |
dc.type | Article | - |
dc.publisher.location | 미국 | - |
dc.identifier.doi | 10.1172/jci176631 | - |
dc.identifier.bibliographicCitation | Journal of Clinical Investigation | - |
dc.citation.title | Journal of Clinical Investigation | - |
dc.description.isOpenAccess | N | - |
dc.description.journalRegisteredClass | scie | - |
dc.description.journalRegisteredClass | scopus | - |
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