Synaptogenesis
Synaptogenesis is the formation of synapses between neurons in the nervous system. Although it occurs throughout a healthy person's lifespan, an explosion of synapse formation occurs during early brain development, known as exuberant synaptogenesis. 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. Processes that are not used, or inhibited during their critical period will fail to develop normally later on in life.
Exuberant synaptogenesis
Brain growth and development begins during gestation and into the postnatal period. Brain development can be divided into stages including: neurogenesis, differentiation, proliferation, migration, synaptogenesis, gliogenesis and myelination, and apoptosis and synaptic pruning. Synaptogenesis occurs in the third trimester during gestation as well as the first two years postnatal. During neuron differentiation, growth cones that extend off the tip of each axon act as the site for elongation of each axon. These growth cones find signal molecules which act as guidance cues and form synapses. Connections formed between neurites may be random or selective.Exuberant synaptogenesis is characterized by a few characteristics. First, it involves the formation of long axonal projections, and an overproduction of small axonal branches, synapses, and dendritic branches and/or spines. Throughout this process, many of these structures may be maintained or eventually eliminated. Elimination may occur by neuronal death or selective deletion.
Developmental exuberance may occur macro- or microscopically. Macroscopic exuberance occurs when transient projections are formed between macroscopic regions in the brain. In comparison, microscopic exuberance occurs when transient structures involved in communication between neurons forms.
Signaling molecules
UNC-4 transcription factor
What specific molecules and chemical signals are involved in synaptogenesis has yet to be fully understood. Some evidence posits that transcription factors are heavily involved in directing where axons and dendrites form synapses before and after synaptogenesis. The main study focusing on this involved motor neurons of C.elegans. In this study, researchers found that knockout animals without the gene, unc-4 have motor defects specifically with moving backwards. This gene is necessary for the Prd-like homeodomain transcription factor. These animals also had abnormal synaptic specificity indicating that this transcription factor is likely involved in determining where and how synapses are formed.Other studies found that this transcription factor was involved in synaptic strength. In this study, it was found that the unc-4 pathway negatively regulates ceh-12, a gene involved in regulating synaptic choice.
Growth cones and guidance cues
Guidance cues are essential for nervous system development as well as synaptic maintenance and remodeling. Guidance cues--attractive or repulsive--are sensed by growth cones. Expression of guidance cue genes is mediated at the transcriptional, post-transcriptional, translational, and post-translational levels.Most guidance cues converge onto various families of small GTPases which go back and forth from active to inactive forms. There are a multitude of signaling pathways involved in this process but the key ones involve netrins and fibronectin leucine-rich repeat transmembrane proteins, the Slit family, semamorphins, ephrin, non-canonical genes, and RTN4 receptors.
Netrin and FLRTs signaling pathways
NTNs and FLRTs both act as guidance cues. NTNs may act as attractants or repellents by DCC and neogenin1, or repellants by UNC5 receptors. UNC5s also act as repulsive receptors for FLRTs. Besides guidance cues, NTNs and FLRTs are also involved in synaptic specificity and synaptogenesis.In studying Netrin, one study found that Netrin is not needed for long-range guidance decision, but is used for short-range synaptic targeting. This was determined from studying an RP3 axon, which expresses Netrin as an axonal guidance cue. In gene knockout studies of Netrin, the RP3 growth cone still formed the correct synapses but the connections were not strong.
Elimination Mechanisms of Transient Projections
In exuberant synaptogenesis, many of the projections formed are eliminated either by neuronal death or selective deletion.By using retrograde tracing to label transient projections, researchers were able to detect the mechanism of selection axonal deletion. Most of the evidence is provided from studying axonal elimination in the visual cortex, so more research is necessary. However, current research proposes that this elimination mechanism involves retraction of branches over short distances in addition to degeneration of long branches.
The main question that researchers are asking is: what triggers axonal elimination of exuberant synapses? In one study, researchers determined that mice mutant for semaphorin, a molecule that is chemorepulsive to growth cones, had defective pruning in hippocampal mossy fibers. Other chemorepulsive molecules include Slits and ephrins.
Synaptic adhesion molecules (SAMs)
Synaptic adhesion molecules have been presented by researchers as potentially key molecules involved in the organization of synaptic junctions. SAMs are involved in pre- to postsynaptic signaling and the reverse direction.Distribution
SAMs often form heterophilic complexes that differ based on location. For example, presynaptic SAMs are present on excitatory and inhibitory synapses. In comparison, post synaptic SAMs are very diverse and are specific for excitatory or inhibitory synapses.Classification
The most well-studied SAMs involved in developing and mature synapses include neurexins and neuroligins, EphBs and ephrin-Bs, immunoglobulin -containing cell adhesion molecules and cadherins.Neurexins and neuroligins
Studies demonstrate that both neurexins and neuroligins are involved in excitatory and inhibitory synapse formation. Neurexin-neuroligin interactions are also involved in the organization of pre- and postsynaptic terminal components.There are various subtypes of neurexins and neuroligins which determine their involvement in either excitatory or inhibitory synapse formation. α- and β-neurexin have similar intracellular domains but different sized extracellular domains. Neuroligins bind to neurexins. Neuroligin 1 is involved in excitatory specializations formation, but it depends on the results of alternative splicing. Neuroligin 2 is localized to inhibitory synapses. Neuroligin 3 is likely involved in excitatory synaptogenesis, but more research needs to be conducted on this. However, one study found that knockdown of all neuroligins leads to a decrease in frequency of inhibitory but not excitatory miniature synaptic currents. Both neurexin and neuroligins have a PDZ binding domain that determines what synaptic scaffolding proteins they interact with.
Another important role of neuroligins and neurexins is the determination of where a synapse forms. For example, co-clustering of neuroligin 1 to PSD-95 acts as a hotspot for presynaptic machinery.
EphBs and Ephrin-Bs
Ephs can be divided into A and B subclasses based on affinity for ephrin-A or ephrin-B ligands. Studies reveal that mainly EphB-ephrin-B interactions are involved in synaptogenesis.The binding of EphB to Ephrin-B leads to bidirectional signaling and contact-mediated transcellular signaling. During development, this interaction is primarily involved in axon guidance and boundary formation. However, these signaling molecules have also been shown to modify postsynaptic organization.
EphBs are particularly involved in excitatory synaptogenesis. 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. Lastly, binding of Ephrin-B to EphB2 leads to interactions between the extracellular domains of the NMDAR and EphB2.
Immunoglobulins
A key characteristic of Ig molecules is the diverse number of globular extracellular cysteine-looped domains. A number of members of the Ig superfamily have been identified as essential molecules for the organization of pre and post synaptic domains. These include synaptic cell adhesion molecules, synaptic adhesion-like molecules, netrin G2 ligand, neural cell adhesion molecule, etc.| Immunoglobulin superfamily type | Function |
| Synaptic cell adhesion molecules | Regulation of the number of presynaptic specializations, and mediation of cell adhesion independently of calcium. |
| Synaptic adhesion-like molecules | Plays a role in synapse maturation, neurite outgrowth during development, AMPAR clustering, PSD-95-containing synaptic site formation, and the regulation of the formation of excitatory synaptic sites. |
| Netrin G2 ligand | Promotes dendritic spine formation, clustering of PSD-95 and NMDARs, triggering of presynaptic differentiation, formation of excitatory synapses. |
| Neural cell adhesion molecule | Not necessary for synaptogenesis, but hypothesized to play a role in axon guidance. |