Species-conserved SYNGAP1 phenotypes associated with neurodevelopmental disorders

Abstract

SYNGAP1 loss-of-function variants are causally associated with intellectual disability, severe epilepsy, autism spectrum disorder and schizophrenia. While there are hundreds of genetic risk factors for neurodevelopmental disorders (NDDs), this gene is somewhat unique because of the frequency and penetrance of loss-of-function variants found in patients combined with the range of brain disorders associated with SYNGAP1 pathogenicity. These clinical findings indicate that SYNGAP1 regulates fundamental neurodevelopmental processes that are necessary for brain development. Here, we describe four phenotypic domains that are controlled by Syngap1 expression across vertebrate species. Two domains, the maturation of cognitive functions and maintenance of excitatory-inhibitory balance, are defined exclusively through a review of the current literature. Two additional domains are defined by integrating the current literature with new data indicating that SYNGAP1/Syngap1 regulates innate survival behaviors and brain structure. These four phenotypic domains are commonly disrupted in NDDs, suggesting that a deeper understanding of developmental Syngap1 functions will be generalizable to other NDDs of known or unknown etiology. Therefore, we discuss the known molecular and cellular functions of Syngap1 and consider how these functions may contribute to the emergence of disease-relevant phenotypes. Finally, we identify major unexplored areas of Syngap1 neurobiology and discuss how a deeper understanding of this gene may uncover general principles of NDD pathobiology.

Comprehensive behavioral analysis of heterozygous Syngap1 knockout mice

“…In heterozygous Syngap1 knockout ( Syngap1 −/+ ) mice, robust changes in behavioral phenotypes have been reported by several groups (see Table S4). Syngap1 −/+ mice show increased locomotor activity , decreased anxiety‐like behavior , impaired reference spatial memory , and impaired working spatial memory . In addition, increased stereotypic behavior , decreases in motor functions in females , elevated startle response and a decrease in prepulse inhibition , reduced social novelty preference , and impaired cued fear memory have been reported by preceding studies.…”

“…While many studies have shown elevated locomotor activities of Syngap1 −/+ mice in novel environments in various behavioral tests , activity in familiar environment has not yet been tested . In the present study, we observed the home cage locomotor activity of these mice and found that they have a significantly increased locomotor activity at night, which indicates that these mice show hyperlocomotor activity not only in novel, but also in familiar environments.…”

“…In this study, female Syngap1 −/+ mice were not tested. Several previous studies have reported that many behavioral phenotypes were shared between male and female Syngap1 −/+ mice , while Muhia et al reported a decreased latency to fall in the rotarod test only in females . Further studies are necessary to clarify the effect of sex on the phenotypes of the Syngap1 −/+ mouse line that we used in the present study.…”

“…Guo et al also argued that mutant mice did not properly perceive danger, and the increased open‐arm time was not related to a generalized or novelty‐induced hyperactivity, because there were no differences between genotypes in the number of open or total arm entries. On the other hand, Kilinc et al claimed that it was unclear if the increased time in the open arms of the mutant mice reflects reduced anxiety or an increased exploratory drive, or both. Overall, it is still unclear whether Syngap1 −/+ mice have a decreased anxiety.…”

Plasticity of dendritic spines: Molecular function and dysfunction in neurodevelopmental disorders

“…This delocalization of SynGAP may help to transiently increase Ras activity in stimulated spines, thereby stabilizing LTP. Indeed, the active form of Ras (Ras‐GTP) was increased in synapses after LTP induction, and restoring normal SynGAP protein levels in SYNGAP1 heterozygous knockout mice rescued both LTP and Ras‐related signaling impairments . In addition, SynGAP has been shown to suppress spine formation and maturation.…”