Abstract
Netrin-G2 is a membrane-anchored protein known to play critical roles in neuronal circuit development and synaptic organization.In this study,we identify compound heterozygous mutations of c.547deIC,p.(Arg183Alafs*186)and c.605G＞A,p.(Trp202X)in NTNG2 causing a syndrome exhibiting developmental delay,intellectual disability,hypotonia,and facial dysmorphism.To elucidate the underlying cellular and molecular mechanisms,CRISPR-Cas9 technology is employed to generate a knock-in mouse model expressing the R183Afs and W202X mutations.We report that the Ntng2R183Afs/W202X mice exhibit hypo-tonia and impaired learning and memory.We find that the levels of CaMKⅡ and p-GluA1Ser831 are decreased,and excitatory postsynaptic transmission and long-term potentiation are impaired.To increase the activity of CaMKⅡ,the mutant mice receive intraperitoneal injections of DCP-LA,a CaMKⅡ agonist,and show improved cognitive function.Together,our findings reveal molecular mechanisms of how NTNG2 deficiency leads to impairments of cognitive ability and synaptic plasticity.
万方数据