The Noonan Syndrome-Associated D61G Variant Of SHP2 Prevents Synaptic Scaling Down

Homeostasis plasticity,including scaling up and scaling down,is of great important for maintaining the stability of neural circuits and balancing the negative effects of long-term synaptic strength changes.One of the important features of synapse scaling down is the reduction of synaptic strength,including protein loss from postsynaptic site and decreased surface AMPA receptors.Previous studies have revealed that Src homology 2 domain containing tyrosine phosphatase 2(SHP2)plays an important role in AMPA receptors trafficking in synaptic plasticity and synaptic scaling up.However,the role of SHP2 in synaptic down-scaling remains largely unknown.Further interpretation will help us to target the treatment of neurological diseases related to SHP2 dysregulation,such as Noonan syndrome.Here,we treated cultured neurons with bicuculline(Bic)to induce synaptic scaling down.Using biochemical approach and cell imaging,we further found that chronic Bic treatment elicited a time dependent down regulation of surface expression of AMPA receptors which induced a synaptic downscaling.Moreover,the interaction between SHP2 and PSD95 decreased in a time-caused dependent manner,which in turn caused the reduction of synaptic content of SHP2 during synaptic downscaling.In addition,utilizing the adeno-associated virus(AAVs)-mediated overexpression system,we found that the prevented dispersion of SHP2 at postsynaptic sites after down-scaling may due to the Noonan syndrome-associated genetic variant SHP2-D61 G enhances the association with PSD95,which leads to the deficient of internalization of AMPA receptors and causes impaired synaptic down-scaling.Collectively,our finding reveals a molecular mechanism of the Noonan syndrome-associated genetic variant SHP2-D61 G that contributes to deficient synaptic downscaling,thereby advancing our understanding of homeostatic plasticity.