The secrets of a functional synapse--from a computational and experimental viewpoint

Abstract

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.

Figure 1

A scheme for kinesin attached to mictotubules (MT) and to a vesicle. The molecule is composed of two heads (marked by an arrow) that allow attachment to MT, a central coiled region and a region which connects the molecule to the intracellular vesicle to be moved. The movement is based on ATP hydrolysis by the head motor domain. Adaptor and receptors associated with the cargo vesicles (SV, synaptic vesicle; Mito, mitochondria; APP, Amyloid precursor protein) provide another strategy to enrich motor-cargo combinations.

Figure 2

A schematic view of an ACh synapse. Molecules that specify the NT phenotype are marked A-F. A, a representative of ACh ligand binding receptor family; B, muscarinic ACh receptor as presynaptic autoinhibitors; C, Acetylcolinesterase, AchE; D, Choline high affinity transporter; E, Choline Acetyle Transferase, ChAT; F, Vesicular ACh transporter, VAChT. E and F proteins comprise the 'cholinergic locus' (see text).

Figure 3

A visualization and annotation of a genomic region in the vicinity of the 'cholinergic locus' at chromosome 10 (in human). For more information on the visualization, see [36]. Orange lined boxes mark the exons of the ChAT and several of the alternative transcripts. The orange bar indicates the entire length of the first ChAT non-coding exon. The level of conservation among Human-Mouse-Chimp-Rat-Dog-Chicken-Fugu and Zebrafish is shown graphically by the height of the conservation histogram. The pairwise conservation with human is depicted by the scale from black (high) to low (white) for each of the listed organisms. Note that the level of conservation in human-mouse-rat-Fugu extends beyond the coding region of VAChT (semi-transparent orange box).