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

Abstract

RAS/MAPIC 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 (IC499E) discovered in RASopathy patients. We found expressing BRAF IC499E (ICE) in neural stem cells under the control of a Nestin-Cre promoter (Nestin;BRAFICE/+) induced hippocampal memory deficits, but expressing it in excitatory or inhibitory neurons did not. BRAF ICE 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 ICE also showed reactive astrogliosis. Astrocyte-specific adeno-associated virus-BRAF ICE (AAV-BRAF ICE) delivery induced memory deficits and reactive astrogliosis and increased astrocytic Ca2+fluctuations. Notably, reducing extracellular signal-regulated kinase (ERIC) activity in astrocytes rescued the memory deficits and altered astrocytic Ca2+ activity of Nestin;BRAFICE/+ mice. Furthermore, reducing astrocyte Ca2+ activity rescued the spatial memory impairments of BRAF ICE-expressing mice. Our results demonstrate that ERIC hyperactivity contributes to astrocyte dysfunction associated with Ca2+ dysregulation, leading to the memory deficits of BRAF-associated RASopathies.