This modification disrupted the physical interaction between PSD95 and the N-methyl-D-aspartate receptor (NMDAR) NR2B and NR2A subunits, leading to a reduction in NMDAR-mediated synaptic currents and neuronal hyperexcitability.<h4>Conclusions</h4>Our findings identify HSDL2 as a novel endogenous antiseizure protein that confers protection in epilepsy by modulating synaptic excitability. Here, GRIN2A is linked to epilepsy.