SYNGAP1

Synaptic Ras GTPase-activating protein 1, also known as synaptic Ras-GAP 1 or SYNGAP1, is a is_associated_with::protein that in humans is encoded by the SYNGAP1 is_associated_with::gene. SYNGAP1 is a ras GTPase-activating protein that is critical for the development of cognition and proper synapse function. Mutations in humans cause is_associated_with::intellectual disability.

Function
SynGAP1 is a complex protein with several functions that may be regulated temporally via complex isoforms. A well documented function of SynGAP1 involves is_associated_with::NMDA receptor mediated synaptic plasticity and membrane insertion of is_associated_with::AMPA receptors through the suppression of upstream signaling pathways. However, SynGAP1 has also been shown to function cooperatively with Unc51.1 in is_associated_with::axon formation. One way SynGAP1 affects these processes is through the MAP kinase signaling pathway by attenuation of Ras signalling. However, is_associated_with::alternative splicing and multiple translational start sites have been shown to cause opposing effects, illustrating the importance of multiple functional domains that reside within the c- and n-termini. For example, the expression of an α1 or α2 c-terminal variant of SynGAP1 will either increase or decrease synaptic strength, respectively. Overall, SynGAP1 is essential for development and survival, which is evident as knockout mice die perinatally.

Dendritic spine development and maturation
SynGAP1 is shown to localize at the is_associated_with::postsynaptic density on the is_associated_with::dendritic spines of excitatory synapses. Cultured neurons of SynGAP heterozygotic and homozygotic knockout mice display accelerated maturation of is_associated_with::dendritic spines, including an increase in overall spine size, which produces more mushroom shaped and less stubby spines. Spine heads are enlarged due to the increased is_associated_with::phosphorylation of is_associated_with::cofilin, leading to a decrease in F-is_associated_with::actin severing and turnover. The increased size of the dendritic spines also corresponded to an increase in membrane bound AMPARs or a decrease in is_associated_with::silent synapses. These neurons displayed a higher frequency and larger amplitudes of miniature is_associated_with::excitatory postsynaptic potentials (mEPSP). Mice models with domain specific mutations led to neonatal hyperactivity of the hippocampal trisynaptic circuit. is_associated_with::Mutations had the greatest impact during the first 3 weeks of development, and reversal of mutations in adults did not improve behavior and cognition.

Clinical significance
Several mutations in the SYNGAP1 gene were identified as the cause of intellectual disability. Intellectual disability is sometimes associated with syndromes of other defects caused by the same gene, but SYNGAP1-associated intellectual disability is not; it is therefore called non-syndromic intellectual disability. Since neither of the parents of children with this condition have the mutation, this means it was a sporadic mutation that occurred during division of the parents' gametes (is_associated_with::meiosis) or fertilization of the egg. It is a dominant mutation, which means that the individual will be developmentally disabled even if only one is_associated_with::allele is mutated.

Mutations in this gene have also been found associated to cases of epileptic encephalopathies. (doi: 10.1038/ng.2646)

Interactions
SYNGAP1 has been shown to interact with is_associated_with::DLG3 and is_associated_with::ULK1.