Abstract
In humans, copy number variations in CYFIP1 appear to have sweeping physiological and structural consequences in the brain, either producing or altering the severity of intellectual disability, autism, and schizophrenia. Independently, SynGAP1 haploinsufficiency produces intellectual disability and, frequently, autism. Cyfip1 inhibits protein translation and promotes actin polymerization, and SynGAP1 is a synaptically localized Ras/Rap GAP. While these proteins are clearly distinct, studies investigating their functions in mice have shown that each regulates the maturation of synapses in the hippocampus and haploinsufficiency for either produces an exaggerated form of mGluR-dependent long-term depression, suggesting that some signaling pathways converge. In this study, we examined how Cyfip1 haploinsufficiency impacts SynGAP1 levels and localization, as well as potential sites for mechanistic interaction in mouse hippocampus. The data show that synaptic, but not total, levels of SynGAP1 in Cyfip1+/– mice were abnormally low during early postnatal development and in adults. This may be in response to a shift in the balance of kinases that activate SynGAP1 as levels of Cdk5 were reduced and those of activated CaMKII were maintained in Cyfip1+/– mice compared to wild-type mice. Alternatively, this could reflect altered actin dynamics as Rac1 activity in Cyfip1+/– hippocampus was boosted significantly compared to wild-type mice, and levels of synaptic F-actin were generally enhanced due in part to an increase in the activity of the WAVE regulatory complex. Decreased synaptic SynGAP1 coupled with a CaMKII-mediated bias toward Rap1 inactivation at synapses is also consistent with increased levels of synaptic GluA2, increased AMPA receptor-mediated responses to stimulation, and increased levels of synaptic mGluR1/5 compared to wild-type mice. Collectively, our data suggest that Cyfip1 regulates SynGAP1 and the two proteins work coordinately at synapses to appropriately direct actin polymerization and GAP activity.
Highlights
Appropriate levels and regulation of Cyfip1 are important for brain development and function
These findings suggest that there may be fewer synapses in Cyfip1+/− hippocampus, but this is unlikely based on previous experiments, which showed that at this age, the density of immunolabeled presynaptic terminal puncta in tissue sections from hippocampal CA1 was similar in Cyfip1+/− and Wt, and that miniature excitatory postsynaptic current frequency in CA1 stratum radiatum was increased in Cyfip1+/− mice at P10 compared with Wt (Hsiao et al, 2016)
But by a different mechanism, a separate study has shown data suggesting that decreased levels of synaptic SynGAP1 can open “slots” in PSD95, permitting interactions with alternate partners and promoting a change in postsynaptic densities (PSDs) composition (Walkup et al, 2016; Lautz et al, 2018)
Summary
Appropriate levels and regulation of Cyfip are important for brain development and function. Cyfip manipulation has strong anatomical, cellular, and physiological consequences that overlap mechanistically with cell signaling pathways employed by other genes relevant to intellectual disability, autism, and schizophrenia (Bozdagi et al, 2012; Dominguez-Iturza et al, 2019; Fricano-Kugler et al, 2019; Silva et al, 2019) Such studies suggest that Cyfip1-regulated pathways are part of a nexus of vulnerable developmental events. An example of this is that mice haploinsufficient for Cyfip show greatly enhanced mGluR1/5-dependent long-term depression (LTD) in the hippocampus that is independent of the usual requirement for protein synthesis (Bozdagi et al, 2012). Whether or how SynGAP and Cyfip regulatory pathways are related has not been investigated
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