Correction of SynGAP haplodeficiency-related defects in AMPA receptor dynamic nanoscale organization

Pathogenic SYNGAP gene mutations generally lead to haploinsufficiency and account for up to 1% of intellectual disability cases. SynGAP is one of the most abundant postsynaptic proteins that maintains a low basal activity in excitatory synapses. It acts through AMPA type glutamate receptors (AMPAR) that mediate most fast excitatory neurotransmission in the brain.

In SynGAP haplodeficiency, AMPAR trafficking and surface expression are dysregulated, and synaptic plasticity is impaired.

In our project, we aim to 1) study how SynGAP regulates the surface nano-organization of AMPAR subunits, 2) validate a novel strategy to stabilize SynGAP in the postsynaptic region using innovative molecular tools, 3) exploit our strategy as well as pharmacological approaches to restore normal synaptic transmission and plasticity in SynGAP+/- neurons.We will use recently developed and validated antibody fragments against each AMPAR subunit with 4-color dSTORM/U-PAINT microscopy to uncover their specific nanoscale co-organization.

Furthermore, we will test novel synthetic nanobodies specific to calcium permeable receptors to provide the first direct microscopy evidence on their synaptic distribution, in relation to SynGAP haplodeficiency.

We will test a newly engineered family of proteins created in our group that aims to stabilize the complex of PSD95 and SynGAP to counter the loss of half the SynGAP protein in haplodeficient neurons, at different time windows as SynGAP affects neuronal maturation and synaptic development.

We will also aim to reverse the upregulation of calcium permeable AMPARs observed in SynGAP haploinsufficiency by selectively blocking them with NASPM.

Together, our expected results will provide unprecedented insight to the regulation of excitatory synapses, as well as novel strategies to experimentally correct SynGAP haplodeficiency.