Abstract
SynGAP is a postsynaptic density (PSD) protein that binds to PDZ domains of the scaffold protein PSD-95. We previously reported that heterozygous deletion of Syngap1 in mice is correlated with increased steady-state levels of other key PSD proteins that bind PSD-95, although the level of PSD-95 remains constant (Walkup et al., 2016). For example, the ratio to PSD-95 of Transmembrane AMPA-Receptor-associated Proteins (TARPs), which mediate binding of AMPA-type glutamate receptors to PSD-95, was increased in young Syngap1+/-mice. Here we show that only females and not males show a highly significant correlation between an increase in TARP and a decrease in synGAP in the PSDs of Syngap1+/-rodents. The data reveal a sex difference in the adaptation of the PSD scaffold to synGAP haploinsufficiency.
Highlights
SynGAP is a Ras/Rap GTPase Activating Protein that is expressed in neurons and is highly concentrated in the postsynaptic density (PSD) of glutamatergic synapses in the brain (Chen et al, 1998; Kim et al, 1998)
The synGAP/PSD-95 ratio (Figure 2A, left) is reduced by 22% in HET rodents compared to wild type (WT)
The ratio of Transmembrane AMPA-Receptor-associated Proteins (TARPs) to PSD-95 (Figure 2B, left) is not significantly different, even when the results were averaged for animals grouped by sex, species, and age (Figure 2A and B), except for seven wk old female mice in which the ratio of TARPs to PSD-95 was significantly reduced compared to WT
Summary
SynGAP is a Ras/Rap GTPase Activating Protein that is expressed in neurons and is highly concentrated in the postsynaptic density (PSD) of glutamatergic synapses in the brain (Chen et al, 1998; Kim et al, 1998). One function of synGAP is to regulate the balance of active Ras and Rap at the postsynaptic membrane (Walkup et al, 2015), thereby controlling the balance of exocytosis and endocytosis of AMPA-type glutamate receptors (Zhu et al, 2002) and contributing to regulation of the actin cytoskeleton (Tolias et al, 2005). In a recent paper in eLife (Walkup et al, 2016), we postulated that synGAP helps to regulate anchoring of AMPA-type glutamate receptors (AMPARs) in the PSD. An early event in induction of long-term potentiation (LTP) is increased trapping of AMPARs that is mediated by enhanced binding of TARPs to PDZ domains (Opazo and Choquet, 2011; Tomita et al, 2005).
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
