Transsynaptic modality codes in the brain: possible involvement of synchronized spike timing, microRNAs, exosomes and epigenetic processes

John Smythies, Lawrence Edelstein

This paper surveys two different mechanisms by which a presynaptic cell can modulate the structure and function of the postsynaptic cell. We first present the evidence that this occurs, and then discuss two mechanisms that could bring this about. The first hypothesis relates to the long lasting effects that the spike patterns of presynaptic axons may exert by modulating activity-inducible programs in postsynaptic cells. The second hypothesis is based on recently obtained evidence that, the afferent neuron at the neuromuscular junction buds off exosomes at its synapse and carries a cargo of Wg and Evi, which are large molecular transsynaptic signaling agents (LMTSAs). Further evidence indicates that many types of neurons bud off exosomes containing payloads of various lipids, proteins, and types of RNA. The evidence suggests that they are transmitted across the synapse and are taken up by the postsynaptic structure either by perisynaptic or exosynaptic mechanisms, thus mediating the transfer of information between neurons. To date, the molecular hypothesis has been limited to local interactions within the synapse of concern. In this paper, we explore the possibility that this represents a mechanism for information transfer involving the postsynaptic neuron as a whole. This entails a review of the known functions of these molecules in neuronal physiology, together with an estimate of the possible types of information they could carry and how they might affect neurocomputations.