Abstract
Experience-dependent synaptic plasticity refines brain circuits during development. To identify novel protein synthesis-dependent mechanisms contributing to experience-dependent plasticity, we conducted a quantitative proteomic screen of the nascent proteome in response to visual experience in Xenopus optic tectum using bio-orthogonal metabolic labeling (BONCAT). We identified 83 differentially synthesized candidate plasticity proteins (CPPs). The CPPs form strongly interconnected networks and are annotated to a variety of biological functions, including RNA splicing, protein translation, and chromatin remodeling. Functional analysis of select CPPs revealed the requirement for eukaryotic initiation factor three subunit A (eIF3A), fused in sarcoma (FUS), and ribosomal protein s17 (RPS17) in experience-dependent structural plasticity in tectal neurons and behavioral plasticity in tadpoles. These results demonstrate that the nascent proteome is dynamic in response to visual experience and that de novo synthesis of machinery that regulates RNA splicing and protein translation is required for experience-dependent plasticity.
Highlights
The nervous system remodels by changing circuit connectivity in response to sensory experience.This process, known as synaptic plasticity, is thought to be the cellular basis of learning and memory, as well as experience-dependent development of brain circuitry (Cline et al, 1996; Ho et al, 2011; Kandel, 2001; Lamprecht and LeDoux, 2004; Sutton and Schuman, 2006)
To identify newly synthesized proteins (NSPs) that are differentially synthesized in response to visual experience, we conducted quantitative proteomic analysis using dimethyl labeling in combination with BONCAT with method to increase tandem mass spectroscopic (MS/MS)
The MS/MS spectra were searched against three databases, the Uniprot Xenopus laevis database, Xenbase, and PHROG (Wühr et al, 2014), and converted to human homologs according to gene symbol
Summary
The nervous system remodels by changing circuit connectivity in response to sensory experience. Several studies focused on specific candidates based on their known functions in synaptic plasticity, for example alpha calcium/calmodulin-dependent protein kinase type II (aCaMKII), brain-derived neurotrophic factor (BDNF) and cytoplasmic polyadenylation element binding protein (CPEB) (Miller et al, 2002; Schwartz et al, 2011; Shen et al, 2014). These studies demonstrated that regulation of synthesis of individual candidates. RNA splicing and protein translation is itself tightly controlled in response to visual experience, suggesting that de novo synthesis of core cellular machinery is a critical regulatory node for experiencedependent plasticity
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