SYNGAP1: Mind the Gap

Abstract

A cardinal feature of early stages of human brain development centers on the sensory, cognitive, and emotional experiences that shape neuronal-circuit formation and refinement. Consequently, alterations in these processes account for many psychiatric and neurodevelopmental disorders. Neurodevelopment disorders affect 3–4% of the world population. The impact of these disorders presents a major challenge to clinicians, geneticists, and neuroscientists. Mutations that cause neurodevelopmental disorders are commonly found in genes encoding proteins that regulate synaptic function. Investigation of the underlying mechanisms using gain or loss of function approaches has revealed alterations in dendritic spine structure, function, and plasticity, consequently modulating the neuronal circuit formation and thereby raising the possibility of neurodevelopmental disorders resulting from synaptopathies. One such gene, SYNGAP1 (Synaptic Ras-GTPase-activating protein) has been shown to cause Intellectual Disability (ID) with comorbid Autism Spectrum Disorder (ASD) and epilepsy in children. SYNGAP1 is a negative regulator of Ras, Rap and of AMPA receptor trafficking to the postsynaptic membrane, thereby regulating not only synaptic plasticity, but also neuronal homeostasis. Recent studies on the neurophysiology of SYNGAP1, using Syngap1 mouse models, have provided deeper insights into how downstream signaling proteins and synaptic plasticity are regulated by SYNGAP1. This knowledge has led to a better understanding of the function of SYNGAP1 and suggests a potential target during critical period of development when the brain is more susceptible to therapeutic intervention.

RAS Proteins and Their Regulators in Human Disease

“…Furthermore, SYNGAP’s GAP activity against Rap1 requires a C2 domain from SYNGAP1, and the specificity of SYNGAP1 for RAS versus Rap proteins is regulated by phosphorylation by CaM kinase II and CDK5. Loss of SYNGAP1 may, therefore, activate both RAS and Rap proteins to contribute to its effects on neurocognition (Jeyabalan and Clement, 2016). …”

Expansion of the RASopathies

“…Haploinsufficiency in neurofibromin (encoded by the NF1 gene), p120 RasGAP (encoded by the RASA1 gene) and Ras P21 protein activator 2 (encoded by the RASA2 gene) have all been found to cause RASopathies. SynGAP1 (synaptic Ras GTPase activating protein 1) is a recently described RasGAP thought to be expressed only in neurons (for recent review see [37]). Germline mutations in SYNGAP1 have been identified to cause autosomal dominant intellectual disability type 5 which is considered a nonsyndromic form of intellectual disability [38].…”

Analysis of 31-year-old patient with SYNGAP1 gene defect points to importance of variants in broader splice regions and reveals developmental trajectory of SYNGAP1-associated phenotype: case report

“…CaMKII then phosphorylates and activates SYNGAP1 which in turn activates Ras and Rap. This leads to endocytosis of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), a major excitatory neurotransmitter receptor of the central nervous system, and repression of AMPAR trafficking to excitatory postsynaptic membrane [1]. The pathway is the key regulator of synaptic plasticity.…”