Shifting rules in a brain disorder

• 成果类型: Editorial Material
• 署名作者: Choquet, Daniel
• 署名单位: Universite de Bordeaux; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); Centre National de la Recherche Scientifique (CNRS); Institut National de la Sante et de la Recherche Medicale (Inserm); Universite de Bordeaux
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-12477
• DOI: 10.1126/science.adn8707
• 发表日期: 2024-03-01
• 页码: 950-951
• 关键词: syngap

摘要

The mode of action of a synaptic protein is challenged The synaptic Ras/Rap guanosine triphosphatase (GTPase)-activating protein (SynGAP) plays substantial, albeit still elusive, roles in synaptic function (1). SynGAP has attracted considerable attention owing to its pivotal role in modulating excitatory glutamatergic synaptic transmission and neuronal development and because loss-of-function mutations in the SYNGAP1 gene account for up to 1% of genetically based intellectual disabilities. SynGAP comprises two primary functional domains: the GAP domain and the C-terminal domain (CTD). The GAP domain negatively regulates small G protein signaling, which may be crucial for activity-dependent changes in synaptic strength, whereas the CTD binds to postsynaptic density protein 95 (PSD95), but the functional consequences of this are unclear. On page 963 of this issue, Araki et al. (2) reveal that contrary to common belief, GAP domain activity is dispensable for many SynGAP functions and that the CTD is important for the plasticity of synaptic transmission. This suggests that potential therapeutics targeting the GAP domain should be reconsidered.