[1] Synaptogenesis is particularly important during an individual's critical period, during which there is a certain degree of synaptic pruning due to competition for neural growth factors by neurons and synapses.
Brain development can be divided into stages including: neurogenesis, differentiation, proliferation, migration, synaptogenesis, gliogenesis and myelination, and apoptosis and synaptic pruning.
Some evidence posits that transcription factors are heavily involved in directing where axons and dendrites form synapses before and after synaptogenesis.
[9] The most well-studied SAMs involved in developing and mature synapses include neurexins and neuroligins, EphBs and ephrin-Bs, immunoglobulin (Ig)-containing cell adhesion molecules and cadherins.
When activated by soluble ephrin-B-Fc fusion protein, EphB induces clustering of NMDARs and AMPARs, an increase in the number of presynaptic terminals, and the formation of dendritic spines.
[33] The preliminary contact formed between the motor neuron and the myotube generates synaptic transmission almost immediately, but the signal produced is very weak.
[35] After about a week, a fully functional synapse is formed following several types of differentiation in both the post-synaptic muscle cell and the pre-synaptic motor neuron.
[33] The signals that initiate post-synaptic differentiation may be neurotransmitters released directly from the axon to the myotube, or they may arise from changes activated in the extracellular matrix of the synaptic cleft.
Agrin binds to a muscle-specific kinase (MuSK) receptor in the post-synaptic membrane, and this in turn leads to downstream activation of the cytoplasmic protein Rapsyn.
The two signaling molecules released by the axon are calcitonin gene-related peptide (CGRP) and neuregulin, which trigger a series of kinases that eventually lead to transcriptional activation of the AChR genes.
[37] Repression of the AChR gene in the non-synaptic nuclei is an activity-dependent process involving the electrical signal generated by the newly formed synapse.
Because the synapse begins receiving inputs almost immediately after the motoneuron comes into contact with the myotube, the axon quickly generates an action potential and releases ACh.
Evidence for this can be seen in the up-regulation of genes expressing vesicle proteins shortly after synapse formation as well as their localization at the synaptic terminal.
Furthermore, the post-synaptic end plate grows deeper and creates folds through invagination to increase the surface area available for neurotransmitter reception.
In addition, selectivity can be traced to the lateral position that the axons are predeterminately arranged in order to link them to the muscle fiber that they will eventually innervate.
There is evidence for both selective and non-selective paths in synapse formation specificity, leading to the conclusion that the process is a combination of several factors.
At the most basic level, the CNS synapse and the NMJ both have a nerve terminal that is separated from the postsynaptic membrane by a cleft containing specialized extracellular material.
Both structures exhibit localized vesicles at the active sites, clustered receptors at the post-synaptic membrane, and glial cells that encapsulate the entire synaptic cleft.
In terms of synaptogenesis, both synapses exhibit differentiation of the pre- and post-synaptic membranes following initial contact between the two cells.
This includes the clustering of receptors, localized up-regulation of protein synthesis at the active sites, and neuronal pruning through synapse elimination.
For instance, brain-derived neurotrophic factor (BDNF) is produced by the brain and regulates several functions within the developing synapse, including enhancement of transmitter release, increased concentration of vesicles, and cholesterol biosynthesis.
Indeed, a defect in genes encoding neuroligin, a cell-adhesion molecule found in the post-synaptic membrane, has been linked to cases of autism and mental retardation.
[36] The special structure found in the CNS that allows for multiple inputs is the dendritic spine, the highly dynamic site of excitatory synapses.
Recently data have emerged showing that the Wnt protein family has roles in the later development of synapse formation and plasticity.
[44] Wnt-5a performs a similar function on postsynaptic granule cells; this Wnt stimulates receptor assembly and clustering of the scaffolding protein PSD-95.
[44] Furthermore, Wnt7a and Wnt2 signaling after NMDA receptor mediated LTP leads to increased dendritic arborization and regulates activity induced synaptic plasticity.
[46] Blocking Wnt expression in the hippocampus mitigates these activity dependent effects by reducing dendritic arborization and subsequently, synaptic complexity.
[44] In the vertebrate NMJ, motor neuron expression of Wnt-11r contributes to acetylcholine receptor (AChR) clustering in the postsynaptic density of muscle cells.
[45] In motor neurons, Wnt-3 works with Agrin to promote growth cone enlargement, axon branching and synaptic vesicle clustering.
[45][46] Although synaptogenesis occurs more commonly in the developing brain, imaging reveals that approximately 40% of dendritic spines found in the sensory and motor cortices are replaces every 5 days.