Aberrant ERK signaling in astrocytes impairs learning and memory in RASopathy-associated BRAF mutant mouse models

RAS/MAPK pathway mutations often induce RASopathies with overlapping features, such as craniofacial dysmorphology, cardiovascular defects, dermatologic abnormalities, and intellectual disabilities. Although B-Raf proto-oncogene (BRAF) 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 adeno-associated virus-BRAF KE (AAV-BRAF KE) delivery induced memory deficits and reactive astrogliosis and increased astrocytic Ca2+ fluctuations. Notably, reducing extracellular signal-regulated kinase (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.

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Publication Details

Journal
Journal of Clinical Investigation
Published
2025-02-18
DOI
https://doi.org/10.1172/jci176631
Citations
7
Primary Topic
Protein Tyrosine Phosphatases
Type
article
Field-Weighted Citation Impact
5.64

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article

Aberrant ERK signaling in astrocytes impairs learning and memory in RASopathy-associated BRAF mutant mouse models

Myeongjong Yoo, Jung Min Ko, Soo-Whee Kim, Hyungju Park et al.
7 citations
Journal of Clinical Investigation
Protein Tyrosine Phosphatases
5.64
article

Aberrant ERK signaling in astrocytes impairs learning and memory in RASopathy-associated BRAF mutant mouse models

Myeongjong Yoo, Jung Min Ko, Soo-Whee Kim, Hyungju Park, Jaegeon Lee, Dae Hee Han, Soobin Kim, Min-Gyun Kim, Joon‐Yong An, Sunghoe Chang, Sang Jeong Kim, Keun‐Ah Cheon, Ja Eun Choi, Benjamin G. Neel, Pojeong Park, Seoyeon Kim, Kyoung-Doo Hwang, Chul Hoon Kim, Yujin Kim, Yong‐Seok Lee, Kitae Kim, Jihye Choi, Jeongyeon Kim, Jeong Ho Han, Minkyung Kang, Han-Byul Jang, Toshiyuki Araki, Hyun-Hee Ryu, Sun Yong Kim, Bong-Kiun Kaang
article en
7 citations

Abstract

RAS/MAPK pathway mutations often induce RASopathies with overlapping features, such as craniofacial dysmorphology, cardiovascular defects, dermatologic abnormalities, and intellectual disabilities. Although B-Raf proto-oncogene (BRAF) 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 adeno-associated virus-BRAF KE (AAV-BRAF KE) delivery induced memory deficits and reactive astrogliosis and increased astrocytic Ca2+ fluctuations. Notably, reducing extracellular signal-regulated kinase (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.

Journal of Clinical InvestigationVol. 135(8)
Seoul National University (KR), Yonsei University (KR), Korea University (KR), Severance Hospital (KR), New Generation University College (ET), Seoul National University Hospital (KR), NYU Langone Health (US), Integrated Oncology (United States) (US), Korea Brain Research Institute (KR), Yonsei University Health System (KR), Czech Academy of Sciences, Institute of Physiology (CZ)
National Research Foundation of Korea
Openalex Percentile: Top 4%
Protein Tyrosine Phosphatases
5.64
DOIOpen Access PDFOpenAlex
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