GRIN-related disorders (GRD) developmental and epileptic encephalopathies (DEEs) display a clinical spectrum including developmental delay, hypotonia, intellectual disability, epilepsy, and autistic traits. The presence of de novo pathogenic variants in the GRIN genes alters the N-methyl D-aspartate receptor (NMDAR) function, with a genotype-phenotype relationship. Despite recent advances to elucidate GRD pathophysiological mechanisms and to find treatments, to date, GRD therapeutic arms are still scarce and with limited efficacy. Herein, we investigated whether the natural polyamine spermine-positive allosteric modulators of GluN2B subunit-containing NMDARs-or its precursor spermidine might rescue NMDAR hypofunctionality. In heterologous cell systems, administration of spermine potentiated wild-type and loss-of-function (LoF) NMDAR-mediated currents and attenuated synaptic density deficits. Functionally, the putative therapeutic benefit of spermidine (spermine precursor) was assessed in constitutive Grin2b