Editing Synaptogenesis (section)

== 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 [[Myelin|myelination]], and [[apoptosis]] and [[synaptic pruning]].<ref>{{cite journal | vauthors = Rice D, Barone S | title = Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models | journal = Environmental Health Perspectives | volume = 108 Suppl 3 | issue = Suppl 3 | pages = 511–533 | date = June 2000 | pmid = 10852851 | pmc = 1637807 | doi = 10.1289/ehp.00108s3511 | bibcode = 2000EnvHP.108S.511R }}</ref> Synaptogenesis occurs in the third trimester during gestation as well as the first two years postnatal.<ref name="Huttenlocher 1997" /> During neuron differentiation, [[Growth cone|growth cones]] that extend off the tip of each axon act as the site for elongation of each axon.<ref>{{Cite book |url=https://kclpure.kcl.ac.uk/portal/en/publications/the-developing-brain |title=The Developing Brain |vauthors=Brown MC, Keynes R, Lumsden A |date=2001 |publisher=Oxford University Press |isbn=978-0-19-854793-8 |location=Oxford}}</ref> These growth cones find signal molecules which act as guidance cues and form synapses. Connections formed between [[Neurite|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 [[Dendritic spine|spines]]. Throughout this process, many of these structures may be maintained or eventually eliminated. Elimination may occur by neuronal death or selective deletion.<ref name=":5">{{Cite journal |last=Innocenti |first=Giorgio M. |last2=Price |first2=David J. |date=December 2005 |title=Exuberance in the development of cortical networks |url=https://www.nature.com/articles/nrn1790 |journal=Nature Reviews Neuroscience |language=en |volume=6 |issue=12 |pages=955–965 |doi=10.1038/nrn1790 |issn=1471-003X|url-access=subscription }}</ref>  

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.<ref name=":5" /> 

=== 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 factor|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 ''[[Caenorhabditis elegans|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.<ref>{{cite journal | vauthors = Von Stetina SE, Treinin M, Miller DM | title = The motor circuit | journal = International Review of Neurobiology | volume = 69 | pages = 125–167 | date = 2005 | pmid = 16492464 | doi = 10.1016/s0074-7742(05)69005-8 | publisher = Elsevier | isbn = 978-0-12-366870-7 }}</ref>

Other studies found that this transcription factor was involved in synaptic strength. In this study, it was found that the u''nc-4'' pathway negatively regulates ''ceh-12'', a gene involved in regulating synaptic choice.<ref>{{cite journal | vauthors = Von Stetina SE, Fox RM, Watkins KL, Starich TA, Shaw JE, Miller DM | title = UNC-4 represses CEH-12/HB9 to specify synaptic inputs to VA motor neurons in C. elegans | journal = Genes & Development | volume = 21 | issue = 3 | pages = 332–346 | date = February 2007 | pmid = 17289921 | pmc = 1785118 | doi = 10.1101/gad.1502107 }}</ref>

==== Growth cones and guidance cues ====
[[File:Growthcone.jpg|thumb|Image of axonal growth cones ]]
Guidance cues are essential for nervous system development as well as synaptic maintenance and remodeling.<ref name=":0">{{cite journal | vauthors = Yuasa-Kawada J, Kinoshita-Kawada M, Tsuboi Y, Wu JY | title = Neuronal guidance genes in health and diseases | journal = Protein & Cell | volume = 14 | issue = 4 | pages = 238–261 | date = April 2023 | pmid = 36942388 | pmc = 10121128 | doi = 10.1093/procel/pwac030 }}</ref> 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 (NTNs) and fibronectin leucine-rich repeat transmembrane proteins (FLRTs), the ''Slit'' family, semamorphins (SEMA), [[ephrin]], non-canonical genes (morphogens, chemokines, growth factors), and RTN4 receptors.<ref name=":0" />

===== 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.<ref name=":0" />

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.<ref>{{cite journal | vauthors = Mitchell KJ, Doyle JL, Serafini T, Kennedy TE, Tessier-Lavigne M, Goodman CS, Dickson BJ | title = Genetic analysis of Netrin genes in Drosophila: Netrins guide CNS commissural axons and peripheral motor axons | journal = Neuron | volume = 17 | issue = 2 | pages = 203–215 | date = August 1996 | pmid = 8780645 | doi = 10.1016/s0896-6273(00)80153-1 }}</ref>

=== 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.<ref>{{Cite journal |last=Aggoun-Zouaoui |first=Djamila |last2=Innocenti |first2=Giorgio M. |date=December 1994 |title=Juvenile Visual Callosal Axons in Kittens Display Origin‐and Fate‐related Morphology and Distribution of Arbors |url=https://onlinelibrary.wiley.com/doi/10.1111/j.1460-9568.1994.tb00577.x |journal=European Journal of Neuroscience |language=en |volume=6 |issue=12 |pages=1846–1863 |doi=10.1111/j.1460-9568.1994.tb00577.x |issn=0953-816X|url-access=subscription }}</ref>

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 fiber (hippocampus)|mossy fibers]].<ref>{{Cite journal |last=Bagri |first=Anil |last2=Cheng |first2=Hwai-Jong |last3=Yaron |first3=Avraham |last4=Pleasure |first4=Samuel J. |last5=Tessier-Lavigne |first5=Marc |date=May 2003 |title=Stereotyped Pruning of Long Hippocampal Axon Branches Triggered by Retraction Inducers of the Semaphorin Family |journal=Cell |volume=113 |issue=3 |pages=285–299 |doi=10.1016/s0092-8674(03)00267-8 |issn=0092-8674}}</ref> Other chemorepulsive molecules include Slits and ephrins.