FMRP and CYFIP1 at the Synapse and Their Role in Psychiatric Vulnerability
Nicholas E. Clifton, Kerrie L. Thomas, Lawrence S. Wilkinson, Jérémy Hall, Simon Trent
Abstract
There is increasing awareness of the role genetic risk variants have in mediating vulnerability to psychiatric disorders such as schizophrenia and autism. Many of these risk variants encode synaptic proteins, influencing biological pathways of the postsynaptic density and, ultimately, synaptic plasticity. Fragile-X mental retardation 1 (<i>FMR1</i>) and cytoplasmic fragile-X mental retardation protein (FMRP)-interacting protein 1 (<i>CYFIP1</i>) contain 2 such examples of highly penetrant risk variants and encode synaptic proteins with shared functional significance. In this review, we discuss the biological actions of FMRP and CYFIP1, including their regulation of (i) protein synthesis and specifically FMRP targets, (ii) dendritic and spine morphology, and (iii) forms of synaptic plasticity such as long-term depression. We draw upon a range of preclinical studies that have used genetic dosage models of <i>FMR1</i> and <i>CYFIP1</i> to determine their biological function. In parallel, we discuss how clinical studies of fragile X syndrome or 15q11.2 deletion patients have informed our understanding of FMRP and CYFIP1, and highlight the latest psychiatric genomic findings that continue to implicate FMRP and CYFIP1. Lastly, we assess the current limitations in our understanding of FMRP and CYFIP1 biology and how they must be addressed before mechanism-led therapeutic strategies can be developed for psychiatric disorders.