Research progress in SYNGAP1-related neurodevelopmental disorders: from pathogenesis to therapeutic strategies

SYNGAP1-related neurodevelopmental disorder (SRD) is a monogenic inherited brain disorder caused by heterozygous loss-of-function mutations in the SYNGAP1 gene. The clinical presentation is complex, with core features including global developmental delay/intellectual disability, epilepsy, autism spectrum disorder, and various behavioral abnormalities. The SynGAP protein, encoded by the SYNGAP1 gene, is a key regulatory protein in the postsynaptic density of excitatory neurons. Through its GTPase-activating protein activity and structural scaffolding functions, it plays a central role in regulating the Ras/Rap signaling pathways, AMPA receptor trafficking, and maintaining the excitatory/inhibitory balance of neural networks. Haploinsufficiency of SynGAP leads to synaptic plasticity disruption and neural circuit imbalance, thereby triggering a series of neurophysiological and behavioral phenotypes. This article systematically reviews the molecular pathogenesis of SRDs, summarizes advances in treatment from conventional anti-seizure medications to emerging precision therapeutic strategies such as gene supplementation, antisense oligonucleotide-mediated splicing modulation, and translation-activating RNAs, and discusses current research challenges and future directions. Key concepts central to understanding SRDs include the critical developmental periods during which SynGAP exerts its primary influence on synaptic maturation, and cell-type specificity, referring to the differential expression and function of SynGAP in distinct neuronal populations (e.g., excitatory pyramidal neurons vs. parvalbumin-positive interneurons), which underlies circuit-level dysfunction. The aim is to provide a comprehensive perspective for an in-depth understanding of the disease and to support the development of effective therapies.