During neuronal development, extending axons navigate to stereotyped target regions in the brain and body with the ultimate goal of making a functional synaptic connection. The chemical synapse represents a specialized functional and morphological cell structure where a presynaptic neuron communicates with the postsynaptic cell. For most neurons, an action potential in the presynaptic axon stimulates the controlled release of chemical neurotransmitters that bind and activate specific receptor proteins that reside on the postsynaptic and presynaptic membranes. This triggers the opening of ion channels and activation of signaling cascades. There are numerous types of synapses, often characterized by the type of neurotransmitter released from the presynaptic terminal and the specific cell types involved. As a central aspect of neurobiology, there are vast numbers of studies focused on synapse formation, synaptic physiology, and circuit organization and function. The purpose of this article is to focus on recent findings that implicate axon guidance-related proteins in the processes required for synapse formation and plasticity.
Much like axon guidance, the process of forming a new synapse (), or synaptogenesis, involves coordinated cell morphological and structural changes that are instructed through ligand-receptor interactions, intracellular signaling cascades, and complex filamentous actin (F-actin) remodeling. There are also cell intrinsic processes that contribute to the pre-establishment of synaptic components long before the dendrite or axon arrives at future synaptic sites, or that prohibit formation of inappropriate synapses. The processes that govern how, when, and where a synapse will form, and specifically, the cell and molecular mechanisms that control synaptogenesis, are still poorly understood. During the past two decades, technological advances in microscopy and the use of modern molecular and genetic approaches have allowed for basic characterization of key steps in synapse formation and plasticity. Much of our knowledge of synapse formation is based on analysis of either the neuromuscular junction (NMJ) or the glutamatergic axo-dendritic synapse formed between two neurons. However, it is likely that each subtype of synapse, such as an inhibitory (e.g., GABAergic), neuromodulatory (e.g., dopaminergic), or excitatory (e.g., glutamatergic), has distinct mechanisms controlling its formation and plasticity. In fact, there are substantial differences in the processes and molecules involved in the two most studied synapses, the cholinergic NMJ and the glutamatergic central synapse.
Figure 1. Basic steps of axo-dendritic synaptogenesis. Diagrams illustrate key steps involved in forming generic central synapses. (A) A guiding axon and nearby dendrite interact via cell–cell contacts mediated by the growth cone, collateral axon branches, (more ...)
For the purposes of this article, we have chosen to focus in large part on the axo-dendritic synapse as many guidance-related molecules play a role in these types of synapses. For simplicity, we have also organized the basic steps of synapse formation into the following categories: (1) synaptic prepatterning, (2) dendritic filopodial motility, (3) contact stabilization, and (4) synaptic maturation. In addition, functionally mature synapses are not static, but instead alter their strength and number in response to experience to facilitate complex behavioral plasticity.
In this article, we discuss a wealth of literature that indicates an important role for many axon guidance-related proteins in synapse formation and plasticity. Although dual functions for axon guidance molecules in synapse formation may be an efficient use of existing axonal and dendritic proteins, it is interesting how the same proteins can regulate such diverse cell biological processes. Exploring this issue will be an important area for future research.