Excitatory neuron-specific SHP2-ERK signaling network regulates synaptic plasticity and memory

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• RASopathies are neurodevelopmental disorders caused by mutations in RAS signaling pathway components.
• Dysregulation of RAS-extracellular signal-regulated kinase (ERK) signaling is implicated in RASopathies, but cell-type specificity is unclear.
• Noonan syndrome (NS) involves gain-of-function mutations in SHP2 phosphatase (PTPN11).

Purpose of the Study:

• To investigate the cell type-specific contribution of SHP2 mutations to Noonan syndrome phenotypes.
• To elucidate the role of RAS-ERK signaling in excitatory versus inhibitory neurons in the context of NS.

Main Methods:

• Utilized mouse models expressing NS-associated mutant SHP2 (SHP2D61G) in specific neuronal populations.
• Performed transcriptomic analyses to identify SHP2-interacting proteins and their neuronal enrichment.
• Employed dominant-negative mutants to disrupt SHP2-GAB1 interactions and assessed functional outcomes.

Main Results:

• Mutant SHP2D61G expression in excitatory hippocampal neurons increased ERK signaling, impaired long-term potentiation (LTP), and spatial memory.
• SHP2-interacting proteins critical for ERK activation (GAB1, GRB2) were enriched in excitatory neurons.
• Selective disruption of SHP2-GAB1 interaction in excitatory neurons reversed SHP2D61G-induced deficits.
• Ectopic expression of GAB1 and GRB2 with SHP2D61G in inhibitory neurons induced ERK activation.

Conclusions:

• RAS-ERK signaling networks differ significantly between excitatory and inhibitory neurons.
• Excitatory neuron-specific dysregulation of RAS-ERK signaling contributes to the pathophysiology of Noonan syndrome.
• These findings offer insights into the cell type-specific mechanisms underlying RASopathies.