Genetic rescue of disrupted synaptic protein interaction network dynamics following SYNGAP1 reactivation

Abstract

Synaptic protein interaction networks (PINs) dynamically translate neural activity into biochemical signals that regulate synaptic structure and plasticity. Disruption of these coordinated networks is a common feature of autism spectrum disorder (ASD) risk genes, yet it remains unclear whether the molecular organization of a perturbed network can be restored after development. Here, we examined how post-developmental re-expression of the synaptic Ras GTPase-activating protein SynGAP1 affects network structure and signaling dynamics in a conditional SynGAP1 haploinsufficient mouse. Quantitative multiplex co-immunoprecipitation (QMI) across development revealed that SynGAP haploinsufficiency selectively reduced SynGAP-containing complexes without broadly disrupting NMDA-dependent network responses. Tamoxifen-inducible re-expression of SynGAP at postnatal day 21 fully restored both steady-state and activity-dependent interactions within the SynGAP module in hippocampus, and additionally normalized secondary alterations in Shank-Homer scaffolding complexes in somatosensory cortex. These data demonstrate that biochemical restoration of a disrupted synaptic network is achievable, even after early developmental windows have closed. Our findings suggest that while critical periods may constrain functional recovery, molecular network normalization remains possible through genetic reactivation of haploinsufficient synaptic regulators.