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J. Clin. Invest., Feb 18 2025, e176631 | https://doi.org/10.1172/JCI176631
Aberrant ERK signaling in astrocytes impairs learning and memory in RASopathy-associated BRAF mutant mouse models
Minkyung Kang1,2,+, Jihye Choi3,+, Jeongho Han4, Toshiyuki Araki5, Soo-Whee Kim6,7, Hyun-Hee Ryu1, Min-Gyun Kim1,2, Seoyeon Kim6,7, Hanbyul Jang1,2, Sun Yong Kim1,2, Kyoung-Doo Hwang1,2, Soobin Kim1,2, Myeongjong Yoo1,2, Jaegeon Lee1,2, Kitae Kim1,2, Pojeong Park8, Ja Eun Choi8, Dae Hee Han8, Yujin Kim6,7, Jeongyeon Kim9, Sunghoe Chang1,2, Bong-Kiun Kaang8, Jung Min Ko10,11, Keun-Ah Cheon12,13, Joon-Yong An6, Sang Jeong Kim1,2,14, Hyungju Park4, Benjamin G. Neel5, Chul Hoon Kim3*, Yong-Seok Lee1,2,14*
1Department of Physiology, Seoul National University College of Medicine, Seoul, Republic of Korea.
2Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
3Department of Pharmacology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Republic of Korea.
4Research Group of Neurovascular Unit, Korea Brain Research Institute, Daegu, Republic of Korea.
5Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, USA.
6Department of Integrated Biomedical and Life Science, Korea University, Seoul, Republic of Korea.
7BK21FOUR R&E Center for Learning Health Systems, Korea University, Seoul, Republic of Korea.
8School of Biological Sciences, Seoul National University, Seoul, Republic of Korea.
9Emotion, Cognition and Behavior Research group, Korea Brain Research Institute, Daegu, Republic of Korea.
10Department of Pediatrics, Division of Clinical Genetics, Seoul National University College of Medicine, Seoul, Republic of Korea.
11Rare Disease Center, Seoul National University Hospital, Seoul, Republic of Korea.
12Department of Child and Adolescent Psychiatry, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
13Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Yonsei University Health System, Seoul, Republic of Korea.
14Neuroscience Research Institute, Medical Research Center, Seoul National University, Seoul, Republic of Korea.
+These authors contributed equally to this work.
*Corresponding authors: Chul Hoon Kim and Yong-Seok Lee
1Department of Physiology, Seoul National University College of Medicine, Seoul, Republic of Korea.
2Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
3Department of Pharmacology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Republic of Korea.
4Research Group of Neurovascular Unit, Korea Brain Research Institute, Daegu, Republic of Korea.
5Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, USA.
6Department of Integrated Biomedical and Life Science, Korea University, Seoul, Republic of Korea.
7BK21FOUR R&E Center for Learning Health Systems, Korea University, Seoul, Republic of Korea.
8School of Biological Sciences, Seoul National University, Seoul, Republic of Korea.
9Emotion, Cognition and Behavior Research group, Korea Brain Research Institute, Daegu, Republic of Korea.
10Department of Pediatrics, Division of Clinical Genetics, Seoul National University College of Medicine, Seoul, Republic of Korea.
11Rare Disease Center, Seoul National University Hospital, Seoul, Republic of Korea.
12Department of Child and Adolescent Psychiatry, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
13Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Yonsei University Health System, Seoul, Republic of Korea.
14Neuroscience Research Institute, Medical Research Center, Seoul National University, Seoul, Republic of Korea.
+These authors contributed equally to this work.
*Corresponding authors: Chul Hoon Kim and Yong-Seok Lee
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.
논문정보
- Research article
- 2025년 02월 (BRIC 등록일 2025-02-19)
- 국내(교신)+국외 연구진
- 생명과학 > 신경생물학
관련 보도자료
희귀난치성 발달질환에 의한 학습 장애 원인 규명
서울대학교 의과대학 이용석 교수와 연세대학교 의과대학 김철훈 교수로 구성된 공동연구팀이 희귀난치성 발달질환인‘심장-피부-얼굴 증후군’에서 발생하는 학습 및 인지 장애 원인을 규명하였다. 심장-얼굴-피부 증후군 (Cardio-facio-cutaneous syndrome)은 약 810,000명 중 한 명 꼴로 나타나는 희귀난치성 발달질환으로, 명명된 바와 같이 선천성 심장 결함, 안면 기형, 그리고 피부 이상 등을 주요한 증상으로 가진다. 특히 대부분 환자들에게 학습 장애를 포함하는 인지 기능의 장애가 나타나는 것으로 알려져 있다.
- Bio통신원
- 2025. 02. 24
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