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.

Keywords: SYNGAP; autism spectrum disorders; intellectual disability; learning and memory; neurodevelopmental disorders; synaptic plasticity.

Figure 1

Amino acid sequence of human SYNGAP1 and its difference with mouse SYNGAP1. Amino acid sequence differences of SYNGAP1 between Homo sapiens (SYGP1_Human), Rattus rattus (SYGP1_RAT) and Mus musculus (SYGP1_MOUSE). Variations in the sequences were indicated in red colored fonts. Dashed line indicates empty sequences.

Figure 2

SYNGAP1 isoforms arising from alternate splicing. (A) A schematic illustration of potential SYNGAP1 isoforms, which vary in both N- and C-termini. (B) Amino acid sequences that are unique to different N- and C-termini isoforms identified by mass spectrometry (McMahon et al., 2012).

Figure 3

Signaling mechanism upon phosphorylation of SYNGAP1. Schematic model of the cellular events that link CaMKII activity to phosphorylation of SYNGAP1 and its regulation of downstream molecules. Glutamate receptors, such as NMDAR and AMPAR, are clustered at the postsynaptic active zone with a dense matrix called PSD. Upon NMDAR activation, Ca²⁺ enters the postsynaptic cytosol, triggering phosphorylation of CaMKII, which in turn phosphorylates SYNGAP1 (pSYNGAP1). pSYNGAP1 regulates Ras-GTPases controlling actin dynamics and AMPARs insertion into the postsynaptic membrane. In Syngap1 Heterozygous mutation, the inhibition of Ras activation by SYNGAP1 (shown as #) is lost, which increases Ras activity, thereby increasing AMPAR exocytosis to the postsynaptic membrane. Phosphorylation of SYNGAP1 by cyclin-dependent kinase 5 (CDK5) activates Rap1 that increases endocytosis of AMPAR. It is not clear how pSYNGAP1 regulates other SYNGAP1-associated proteins such as Cdc42, Rac1 (dotted orange lines), which are yet to be studied.

Figure 4

Schematic model of the impact of Syngap1 haploinsufficiency on neuronal circuit function. This figure illustrates the impact of Syngap1 heterozygous mutation on dendritic spine morphology, neuronal connection organization, and behavioral phenotypes. Heterozygous mutations in Syngap1 lead to prematuration of dendritic spine morphology during early stages of development (A). This causes abnormal formation and elimination of spines that leads to altered spine density and excitatory neuronal connections during development in the cortex (Aceti et al., 2015). Further, the abnormal cortical excitatory neuronal connections lead to E/I imbalance during early stages of development, which persists, into adult stages in Syngap1 Hets (B). Consequently, these abnormalities bring about altered duration of critical period of development (C), which leads to cognitive and social dysfunction (D). PND, Post-natal Day. The gene products implicated in intellectual disability (ID) and/or autism spectrum disorder (ASD) are marked in Red color text. Some features are modified with permission based on Clement et al. (2012).