Autism-linked protein POSH balances NMDAR signaling via a self-limiting kinase-scaffold loop

POSH (plenty of SH3 domains), an autism-linked scaffold protein, is essential for N-methyl-D-aspartate receptor (NMDAR) complex assembly, and its loss causes ASD-like social deficits in mice. However, the synaptic mechanism remains unclear. Here, we reveal that POSH loss reduces SRC postsynaptic enrichment and weakens the interactions within the SRC-NMDAR-PSD-95 complex. Mechanistically, NMDAR activation triggers RAC1-GTP-dependent recruitment of POSH to membrane, leading NMDAR-induced activation of SRC, a key positive regulator of NMDARs. Notably, prolonged NMDAR activation induces the depletion of both POSH and SRC, establishing a negative feedback loop. This dual spatiotemporal mechanism-transient kinase activation coupled with scaffold degradation-constitutes a self-limiting circuit that prevents NMDAR hyperexcitation. Our findings establish POSH as a molecular rheostat that integrates RAC1-driven membrane targeting with SRC activation to precisely regulate NMDAR signaling. These insights would advance our understanding of synaptic homeostasis and may inform potential therapeutic strategies for ASD and glutamatergic disorders.