Noonan Syndrome-Associated SHP2 Dephosphorylates GluN2B to Regulate NMDA Receptor Function

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Noonan syndrome (NS) is linked to cognitive deficits.
• Hyperactivating mutations in SHP2 phosphatase cause NS.
• The neuronal impact of SHP2 hyperactivation in NS is unclear.

Purpose of the Study:

• Investigate how SHP2 hyperactivation affects neuron function in NS.
• Determine the role of SHP2 in regulating NMDA receptor (NMDAR) function.
• Identify molecular mechanisms linking SHP2 to NMDAR dysfunction in NS.

Main Methods:

• Utilized a mouse model with an NS-associated SHP2 mutation.
• Examined Schaffer collateral-CA1 NMDAR-mediated neurotransmission.
• Performed in vitro and in vivo biochemical assays to identify SHP2 substrates and binding partners.
• Investigated the interaction between phosphorylated GluN2B Y1252 and Nck2.

Main Results:

• NS mice exhibited impaired NMDAR-mediated neurotransmission.
• Reduced contribution of GluN1:GluN2B diheteromers and faster current decay were observed in NS mice.
• Identified GluN2B Y1252 as an SHP2 substrate in vitro and in vivo.
• Phospho-GluN2B Y1252 binds to Nck2, a crucial interaction for NMDAR function.

Conclusions:

• SHP2 and Nck2 are identified as regulators of NMDAR function.
• Altered SHP2 activity impacts NMDAR composition and kinetics.
• NMDAR dysfunction is strongly suggested to contribute to the cognitive deficits observed in Noonan syndrome.