It is estimated than more 6% of all Americans (or nearly 19 million individuals) suffer from a serious mental disorder. Many such disorders arise during development or adolescence, and strong evidence supports that they are caused or exacerbated by gene mutations or variations in gene copy number. Treatments exist, but there are few cures. Human genetic studies have identified CYFIP1 as a gene that is dysregulated in a wide variety of developmental brain disorders including certain forms of Angelman and Prader-Willi syndromes, autism spectrum disorders, and schizophrenia. How does a single gene contribute to so many disorders? CYFIP1 produces a cytoplasmic protein, cytoplasmic FMRP interacting protein (Cyfip1), having two independent and highly conserved functions. Cyfip1 represses cap-dependent translation of FMRP target mRNAs as a noncanonical initiation factor 4E binding protein (4E-BP), and it regulates the generation of branched actin filaments at the plasmalemma as an integral component of the WAVE complex. Regulation of both cap-dependent translation and actin cytoskeleton are known to be important for synapse assembly, morphology, and plasticity and are also known to be pathways that are vulnerable to developmental brain disorders. Thus it is easy to appreciate why loss of even a single copy of Cyfip1 could have broad consequences, but the function of Cyfip1 at developing synapses is not well understood. In this proposal we will investigate how Cyfip1 contributes to synapse development, function, and plasticity using a mouse model we developed expressing reduced levels of Cyfip1. Preliminary experiments show that neurons with reduced Cyfip1 levels display a strong, principally presynaptic phenotype during development that is missing in adolescence, and an equally strong, but postsynaptic phenotype in adolescence that is missing in younger animals. Based on these findings, we will test the hypothesis that Cyfip1's actions in cap-dependent protein synthesis and actin polymerization contribute differentially to presynaptic function during development and postsynaptic physiology and plasticity in maturity.
Several developmental brain disorders have been associated with copy number variation in the gene encoding Cyfip1 and in many cases, altered levels of Cyfip1 correlate with increased disease severity. The proposed experiments will reveal how Cyfip1 regulates synapse function, generation and plasticity of neural circuits.
|Friedman, Lauren G; Riemslagh, Fréderike W; Sullivan, Josefa M et al. (2015) Cadherin-8 expression, synaptic localization, and molecular control of neuronal form in prefrontal corticostriatal circuits. J Comp Neurol 523:75-92|