Figure 8. Distinct roles of individual SynGAP isoforms in neuronal development and synaptic plasticity.

(Α) Schematics illustrating isoform-specific roles for SynGAP in neuronal maturation and synaptic plasticity. SynGAP-β is expressed early in development, has the lowest LLPS propensity resulting in cytosolic localization, possesses the highest GAP activity in cells, and promotes normal dendritic development. SynGAP-β deficiency may be relevant to the neuronal development deficits in neurodevelopmental disorders (NDD). SynGAP-α1 is expressed later in development, undergoes strongest LLPS in spines resulting in dense expression in the PSD at the basal state, and is rapidly dispersed upon synaptic NMDAR-CaMKII activation. SynGAP-α1 deficiency may be relevant to the synaptic plasticity deficits and overconnectivity in NDD. (B) Schematics illustrating the phase-separation and the localization/functions of SynGAP isoforms. SynGAP-α1 is tightly packed at PSD by phase separation and has the ability of low GTPase activations. In contrast, SynGAP-β is less phase-separated and localized more in cytoplasmic region in synapses and dendritic shafts. It has a strong ability of GTPase activation. The phase-separation mutant of SynGAP-α1 LLPS*) behaves similarly to SynGAP-β.