Neuroscience Online (i,9,4)

The establishment of synaptic connections and their maintenance depends the interactions of axons and their targets. These interactions are responsible for synapse stabilization and neuron survival. Synaptic transmission depends on the association of the pre- and post-synaptic elements. The pre- and postsynaptic regions of cells are highly specialized architecturally, which allows for efficient information transfer. The architecture of the synapse is formed during development and can change in an activity-dependent manner.

Molecular Mechanisms of Presynaptic Differentation

Figure 9.18

A growth cone matures into a presynaptic axon terminal. As an axon grows toward its target, its growth cone plays a role in "sensing" attractive and repulsive forces in its local environment. After the axon has reached its target, the terminal matures by altering its shape, the localization of vesicles, and the protein machinery necessary for regulated and constitutive, rather than solely constitutive, secretion. These dramatic changes allow the axon terminal to provide efficient synaptic transmission.

The presynaptic nerve terminal matures from the growth cone and becomes highly specialized to subserve functions necessary for chemical neurotransmission. The presynaptic nerve terminal contains mitochondria and endosomes, although the most striking aspect of this structure is the presence of numerous neurotransmitter-containing synaptic vesicles. Relatively little is known about the molecular mechanisms that underlie differentiation of the presynaptic nerve terminal. It is known that the switch between constitutive vesicle cycling that takes place in the growth cone, and regulated secretion from the mature presynaptic terminal represents a dramatic alteration in function.

Figure 9.19

Scaffolding present on the presynaptic and postsynaptic sides of the synapse helps to mature and align the pre- and postsynaptic elements. For example, neuroligin interacts with neurexin to anchor the pre- and postsynaptic elements together. In addition, the presence of neuroligin enables clustering of synaptic vesicles, suggesting that this protein is involved in presynaptic differentiation. On the postsynaptic side, receptors and some of their signal transducing proteins are anchored in place via direct and indirect (via binding to cytoskeletal binding proteins) interactions with the actin cytoskeleton.

Molecular Mechanisms of Postsynaptic Differentiation

In order for efficient reception of the neurotransmitter signal, the receptors on the postsynaptic cell are clustered at sites opposite the presynaptic active zone. The clustering of postsynaptic receptors is an adaptive behavior that has been studied in detail using the neuromuscular junction as a model system. The nicotinic acetylcholine receptor (AChR) is a ligand-gated ion channel that responds to a signal provided by the neurotransmitter acetylcholine, the transmitter used at the neuromuscular junction. (Additional information about acetylcholine is found in Chapter 12.) AChRs are found at a density of 10,000-20,000/um² in the postsynaptic membrane while there are about 10/um² at extrasynaptic sites. The extraordinary concentration of AChRs at the synapse suggests that the muscle has the capacity to anchor these receptors, while their presence in direct opposition to the presynaptic active zone suggests that the nerve plays a role in organizing the postsynaptic membrane.

Figure 9.20

Differentiation of the synapse involves alterations to both the pre- and postsynaptic sites. The presynaptic terminal must align with a postsynaptic surface and begin to express regulated forms of neurotransmitter secretion. The postsynaptic site must cluster receptors and signal transduction molecules for efficient synaptic transmission.

The cleft separating pre- and postsynaptic membranes contains the basal lamina which coats the entire muscle fiber and is composed of collagens, proteoglycans, and other extracellular matrix molecules including laminin as well as nerve-derived molecules such as agrin (see below). The basal lamina plays a critical role in the assembly of the postsynaptic membrane.