MOUSE MODELS PHENOTYPIC ASSESSMENT, DRUG SCREENING AND PROOF-OF-CONCEPT CLINICAL TRIAL OF GRIN-RELATED DISORDERS

Mutations in GRIN genes encoding NMDAR subunits cause GRIN-related disorders (GRD), a group of developmental encephalopathies. Beyond the use of cellular models to interrogate the functional consequences of GRIN variants, there is an urgent need to develop and characterise GRIN-related disorders (GRD) genetic mouse models covering the GRD genetic and clinical spectrum, to further evaluate the efficacy and safety of novel personalised GRD treatments. To address this clinical need, we characterized Grin2a^+/--LoF, Grin2b^+/--LoF and KI-Grin2a(S1048E)-GoF mouse models. Phenotypic assessment revealed that Grin2b haploinsufficiency alters hippocampal synaptoproteome, provokes synaptic plasticity deficits (LTP disturbance), and impairs motor and cognitive functions. Strikingly, preliminary studies showed that Grin2a^+/- mice displayed only subtle behavioural and electrophysiological alterations (ongoing studies), while KI-Grin2a-GoF mice exhibited mild hippocampal phenotypes, both in brain slices and in cognitive task performance. Further, Grin2b^+/- endophenotypes were used to investigate the potential therapeutic effect of spermidine (SPD), a precursor of spermine (potentiator of GluN2B subunit-containing NMDARs). Chronic SPD administration in young adult Grin2b^+/- mice partially rescued hippocampal LTP deficits in acute brain slices and improved learning and memory along behavioural tasks performance. Based on these preclinical findings, a case study was conducted in two paediatric patients harbouring GRIN2B-LoF variants. Remarkably, one year of spermidine (spermine precursor) treatment improved the adaptive behaviour, with no noticeable side effects. Overall, these findings show the suitability of GRD genetic mouse models for understanding GRD pathophysiology, for testing pharmacoresponsiveness towards defining GRD precision medicine.