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

Area of Science:

• Neuroscience
• Genetics
• Cell Biology

Background:

• RAS/MAPK pathway mutations cause RASopathies with cognitive deficits.
• The specific neural mechanisms underlying BRAF-related cognitive impairment remain unclear.

Purpose of the Study:

• To investigate the neural mechanisms by which BRAF mutations impair cognition in RASopathies.
• To determine the role of astrocytes and calcium signaling in BRAF-associated memory deficits.

Main Methods:

• Utilized mouse models with a gain-of-function BRAF K499E mutation in neural stem cells.
• Examined effects on hippocampal memory, astrogliosis, and astrocytic calcium (Ca2+) activity.
• Employed astrocyte-specific viral delivery and pharmacological inhibition of ERK and Ca2+ signaling.

Main Results:

• BRAF K499E expression in neural stem cells induced hippocampal memory deficits and aberrant reactive astrogliosis.
• Astrocyte dysfunction, including altered Ca2+ fluctuations and reduced long-term depression (LTD), was observed.
• Inhibition of extracellular signal-regulated kinase (ERK) or astrocyte Ca2+ activity rescued memory deficits.

Conclusions:

• ERK hyperactivity in astrocytes contributes to Ca2+ dysregulation and memory deficits in BRAF-associated RASopathies.
• Astrocyte dysfunction is a key mechanism underlying cognitive impairment in these genetic disorders.