Editing Synaptogenesis (section)

=== Classification ===
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. 

==== 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.<ref>{{cite journal | vauthors = Missler M, Südhof TC | title = Neurexins: three genes and 1001 products | journal = Trends in Genetics | volume = 14 | issue = 1 | pages = 20–26 | date = January 1998 | pmid = 9448462 | doi = 10.1016/s0168-9525(97)01324-3 }}</ref> 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.<ref name=":2">{{cite journal | vauthors = Chih B, Engelman H, Scheiffele P | title = Control of excitatory and inhibitory synapse formation by neuroligins | journal = Science | volume = 307 | issue = 5713 | pages = 1324–1328 | date = February 2005 | pmid = 15681343 | doi = 10.1126/science.1107470 | bibcode = 2005Sci...307.1324C }}</ref><ref>{{cite journal | vauthors = Graf ER, Zhang X, Jin SX, Linhoff MW, Craig AM | title = Neurexins induce differentiation of GABA and glutamate postsynaptic specializations via neuroligins | journal = Cell | volume = 119 | issue = 7 | pages = 1013–1026 | date = December 2004 | pmid = 15620359 | doi = 10.1016/j.cell.2004.11.035 | pmc = 2826211 }}</ref> However, one study found that knockdown of all neuroligins leads to a decrease in frequency of inhibitory but not excitatory miniature synaptic currents.<ref name=":2" /> Both neurexin and neuroligins have a PDZ binding domain that determines what synaptic scaffolding proteins they interact with.<ref>{{cite journal | vauthors = Hata Y, Butz S, Südhof TC | title = CASK: a novel dlg/PSD95 homolog with an N-terminal calmodulin-dependent protein kinase domain identified by interaction with neurexins | journal = The Journal of Neuroscience | volume = 16 | issue = 8 | pages = 2488–2494 | date = April 1996 | pmid = 8786425 | doi = 10.1523/jneurosci.16-08-02488.1996 | pmc = 6578772 }}</ref>

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.<ref>{{cite journal | vauthors = Gerrow K, Romorini S, Nabi SM, Colicos MA, Sala C, El-Husseini A | title = A preformed complex of postsynaptic proteins is involved in excitatory synapse development | journal = Neuron | volume = 49 | issue = 4 | pages = 547–562 | date = February 2006 | pmid = 16476664 | doi = 10.1016/j.neuron.2006.01.015 }}</ref>

==== 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.<ref>{{cite journal | vauthors = Kullander K, Klein R | title = Mechanisms and functions of Eph and ephrin signalling | journal = Nature Reviews. Molecular Cell Biology | volume = 3 | issue = 7 | pages = 475–486 | date = July 2002 | pmid = 12094214 | doi = 10.1038/nrm856 }}</ref>

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.<ref>{{cite journal | vauthors = Dalva MB, Takasu MA, Lin MZ, Shamah SM, Hu L, Gale NW, Greenberg ME | title = EphB receptors interact with NMDA receptors and regulate excitatory synapse formation | journal = Cell | volume = 103 | issue = 6 | pages = 945–956 | date = December 2000 | pmid = 11136979 | doi = 10.1016/s0092-8674(00)00197-5 }}</ref><ref>{{cite journal | vauthors = Henkemeyer M, Itkis OS, Ngo M, Hickmott PW, Ethell IM | title = Multiple EphB receptor tyrosine kinases shape dendritic spines in the hippocampus | journal = The Journal of Cell Biology | volume = 163 | issue = 6 | pages = 1313–1326 | date = December 2003 | pmid = 14691139 | doi = 10.1083/jcb.200306033 | pmc = 1435730 }}</ref><ref>{{cite journal | vauthors = Penzes P, Beeser A, Chernoff J, Schiller MR, Eipper BA, Mains RE, Huganir RL | title = Rapid induction of dendritic spine morphogenesis by trans-synaptic ephrinB-EphB receptor activation of the Rho-GEF kalirin | journal = Neuron | volume = 37 | issue = 2 | pages = 263–274 | date = January 2003 | pmid = 12546821 | doi = 10.1016/s0896-6273(02)01168-6 }}</ref> 

==== Immunoglobulins ====
A key characteristic of Ig molecules is the diverse number of globular extracellular cysteine-looped domains.<ref>{{cite journal | vauthors = Rougon G, Hobert O | title = New insights into the diversity and function of neuronal immunoglobulin superfamily molecules | journal = Annual Review of Neuroscience | volume = 26 | issue = 1 | pages = 207–238 | date = March 2003 | pmid = 12598678 | doi = 10.1146/annurev.neuro.26.041002.131014 }}</ref> 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 (SynCAM), synaptic adhesion-like molecules (SALMs), netrin G2 ligand (NGL2), neural cell adhesion molecule (NCAM), etc. 
{| class="wikitable"
|'''Immunoglobulin (Ig) superfamily type'''
|'''Function'''
|-
|Synaptic cell adhesion molecules (SynCAM)
|Regulation of the number of presynaptic specializations, and mediation of cell adhesion independently of calcium.<ref>{{cite journal | vauthors = Biederer T, Sara Y, Mozhayeva M, Atasoy D, Liu X, Kavalali ET, Südhof TC | title = SynCAM, a synaptic adhesion molecule that drives synapse assembly | journal = Science | volume = 297 | issue = 5586 | pages = 1525–1531 | date = August 2002 | pmid = 12202822 | doi = 10.1126/science.1072356 | bibcode = 2002Sci...297.1525B }}</ref>
|-
|Synaptic adhesion-like molecules (SALMs)
|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.<ref>{{cite journal | vauthors = Wang CY, Chang K, Petralia RS, Wang YX, Seabold GK, Wenthold RJ | title = A novel family of adhesion-like molecules that interacts with the NMDA receptor | journal = The Journal of Neuroscience | volume = 26 | issue = 8 | pages = 2174–2183 | date = February 2006 | pmid = 16495444 | doi = 10.1523/jneurosci.3799-05.2006 | pmc = 6674818 }}</ref><ref>{{cite journal | vauthors = Ko J, Kim S, Chung HS, Kim K, Han K, Kim H, Jun H, Kaang BK, Kim E | title = SALM synaptic cell adhesion-like molecules regulate the differentiation of excitatory synapses | journal = Neuron | volume = 50 | issue = 2 | pages = 233–245 | date = April 2006 | pmid = 16630835 | doi = 10.1016/j.neuron.2006.04.005 }}</ref>
|-
|Netrin G2 ligand (NGL2)
|Promotes dendritic spine formation, clustering of PSD-95 and NMDARs, triggering of presynaptic differentiation, formation of excitatory synapses.<ref>{{cite journal | vauthors = Kim S, Burette A, Chung HS, Kwon SK, Woo J, Lee HW, Kim K, Kim H, Weinberg RJ, Kim E | title = NGL family PSD-95-interacting adhesion molecules regulate excitatory synapse formation | journal = Nature Neuroscience | volume = 9 | issue = 10 | pages = 1294–1301 | date = October 2006 | pmid = 16980967 | doi = 10.1038/nn1763 }}</ref>
|-
|Neural cell adhesion molecule (NCAM) 
|Not necessary for synaptogenesis, but hypothesized to play a role in axon guidance.<ref>{{cite journal | vauthors = Dityatev A, Dityateva G, Schachner M | title = Synaptic strength as a function of post- versus presynaptic expression of the neural cell adhesion molecule NCAM | journal = Neuron | volume = 26 | issue = 1 | pages = 207–217 | date = April 2000 | pmid = 10798405 | doi = 10.1016/s0896-6273(00)81151-4 }}</ref>
|}

==== Cadherins ====
Neuronal (N)-cadherins are found in pre and postsynaptic terminals.<ref>{{cite journal | vauthors = Fannon AM, Colman DR | title = A model for central synaptic junctional complex formation based on the differential adhesive specificities of the cadherins | journal = Neuron | volume = 17 | issue = 3 | pages = 423–434 | date = September 1996 | pmid = 8816706 | doi = 10.1016/s0896-6273(00)80175-0 }}</ref> Prior to differentiation, N-cadherins increase in quantity at axon-dendrite contact sites and eventually restrict their presence to sites around the active zone in mature neurons. N-cadherin is also involved in regulating AMPAR trafficking.<ref name=":3">{{cite journal | vauthors = Togashi H, Abe K, Mizoguchi A, Takaoka K, Chisaka O, Takeichi M | title = Cadherin regulates dendritic spine morphogenesis | journal = Neuron | volume = 35 | issue = 1 | pages = 77–89 | date = July 2002 | pmid = 12123610 | doi = 10.1016/s0896-6273(02)00748-1 }}</ref> Besides this, N-cadherin also plays a role in the maturation and stabilization of synaptic specializations. Lastly, N-cadherins help to control dendritic spine morphology and motility.<ref name=":3" />