The Secrets of a Functional Synapse – From a Computational and Experimental Viewpoint

BACKGROUND: Neuronal communication is tightly regulated in time and in space. The neuronal transmission takes place in the nerve terminal, at a specialized structure called the synapse. Following neuronal activation, an electrical signal triggers neurotransmitter (NT) release at the active zone. The process starts by the signal reaching the synapse followed by a fusion of the synaptic vesicle and diffusion of the released NT in the synaptic cleft; the NT then binds to the appropriate receptor, and as a result, a potential change at the target cell membrane is induced. The entire process lasts for only a fraction of a millisecond. An essential property of the synapse is its capacity to undergo biochemical and morphological changes, a phenomenon that is referred to as synaptic plasticity. RESULTS: In this survey, we consider the mammalian brain synapse as our model. We take a cell biological and a molecular perspective to present fundamental properties of the synapse:(i) the accurate and efficient delivery of organelles and material to and from the synapse; (ii) the coordination of gene expression that underlies a particular NT phenotype; (iii) the induction of local protein expression in a subset of stimulated synapses. We describe the computational facet and the formulation of the problem for each of these topics. CONCLUSION: Predicting the behavior of a synapse under changing conditions must incorporate genomics and proteomics information with new approaches in computational biology

Local translation and directional steering in axons

The assembly of functional neural circuits in the developing brain requires neurons to extend axons to the correct targets. This in turn requires the navigating tips of axons to respond appropriately to guidance cues present along the axonal pathway, despite being cellular ‘outposts' far from the soma. Work over the past few years has demonstrated a critical role for local translation within the axon in this process in vitro, making axon guidance another process that requires spatially localized translation, among others such as synaptic plasticity, cell migration, and cell polarity. This article reviews recent findings in local axonal translation and discusses how new protein synthesis may function in growth cone guidance, with a comparative view toward models of local translation in other systems

mTOR signaling in proteostasis and its relevance to autism spectrum disorders

Proteins are extremely labile cellular components, especially at physiological temperatures. The appropriate regulation of protein levels, or proteostasis, is essential for all cells. In the case of highly polarized cells like neurons, proteostasis is also crucial at synapses, where quick confined changes in protein composition occur to support synaptic activity and plasticity. The accurate regulation of those cellular processes controlling protein synthesis and degradation is necessary for proteostasis, and its deregulation has deleterious consequences in brain function. Alterations in those cellular mechanisms supporting synaptic protein homeostasis have been pinpointed in autism spectrum disorders such as tuberous sclerosis, neurofibromatosis 1, PTEN-related disorders, fragile X syndrome, MECP2 disorders and Angelman syndrome. Proteostasis alterations in these disorders share the alterations in mechanistic/mammalian target of rapamycin (mTOR) signaling pathway, an intracellular pathway with key synaptic roles. The aim of the present review is to describe the recent literature on the major cellular mechanisms involved in proteostasis regulation in the synaptic context, and its association with mTOR signaling deregulations in various autism spectrum disorders. Altogether, the cellular and molecular mechanisms in synaptic proteostasis could be the foundation for novel shared therapeutic strategies that would take advantage of targeting common disorder mechanisms.This review was supported by grant BFU2015-68568-P (MINECO/FEDER, EU) to AO