Studying synaptic development and function using C. elegans

Defects in the proper development and function of synapses lead to neurodevelopmental disorders such as Autism and Intellectual Disability, however the molecular mechanisms underlying these processes are still largely unknown. We use the nematode C. elegans, which has a simple and stereotyped nervous system and whose connectome has been fully mapped out, to investigate the conserved molecular mechanisms of synapse development. In particular, we study how presynaptic components including cell adhesion molecules, active zone scaffold proteins, calcium channels and synaptic vesicles arrive at the synapse and form a mature and fully functional presynaptic compartment. We combine the power of worm genetics with high resolution imaging and optical physiology readouts to elucidate the role of key molecules. These approaches have led to discoveries suggesting that the role of synaptic cell adhesion molecules such as Neurexin may be different than initially hypothesized, as we have shown that its role in presynaptic development is independent of extracellular activation and downstream of other initiating factors.

1. Synaptogenic pathways. Kurshan PT, Shen K. Curr Opin Neurobiol. 2019 Aug;57:156-162. doi: 10.1016/j.conb.2019.03.005. Review.
2. γ-Neurexin and Frizzled Mediate Parallel Synapse Assembly Pathways Antagonized by Receptor Endocytosis. Kurshan PT, Merrill SA, Dong Y, Ding C, Hammarlund M, Bai J, Jorgensen EM, Shen K. Neuron. 2018 Oct 10;100(1):150-166.e4. doi: 10.1016/j.neuron.2018.09.007.
3. Clarinet (CLA-1), a novel active zone protein required for synaptic vesicle clustering and release. Xuan Z, Manning L, Nelson J, Richmond JE, Colón-Ramos DA, Shen K, Kurshan PT. Elife. 2017 Nov 21;6. pii: e29276. doi: 10.7554/eLife.29276.
4. Deep phenotyping unveils hidden traits and genetic relations in subtle mutants. San-Miguel A, Kurshan PT, Crane MM, Zhao Y, McGrath PT, Shen K, Lu H. Nat Commun. 2016 Nov 23;7:12990. doi: 10.1038/ncomms12990.
5. Regulation of synaptic extracellular matrix composition is critical for proper synapse morphology. Kurshan PT, Phan AQ, Wang GJ, Crane MM, Lu H, Shen K. J Neurosci. 2014 Sep 17;34(38):12678-89. doi: 10.1523/JNEUROSCI.1183-14.2014.
6. Autonomous screening of C. elegans identifies genes implicated in synaptogenesis. Crane MM, Stirman JN, Ou CY, Kurshan PT, Rehg JM, Shen K, Lu H. Nat Methods. 2012 Oct;9(10):977-80. doi: 10.1038/nmeth.2141.
7. Presynaptic alpha2delta-3 is required for synaptic morphogenesis independent of its Ca2+-channel functions. Kurshan PT, Oztan A, Schwarz TL. Nat Neurosci. 2009 Nov;12(11):1415-23. doi: 10.1038/nn.2417.
8. Mutations in a Drosophila alpha2delta voltage-gated calcium channel subunit reveal a crucial synaptic function. Dickman DK, Kurshan PT, Schwarz TL.
9. A Drosophila kinesin required for synaptic bouton formation and synaptic vesicle transport. Pack-Chung E, Kurshan PT, Dickman DK, Schwarz TL. Nat Neurosci. 2007 Aug;10(8):980-9. J Neurosci. 2008 Jan 2;28(1):31-8. doi: 10.1523/JNEUROSCI.4498-07.2008.
10. Developmental changes in expression patterns of two dopamine receptor genes in mushroom bodies of the honeybee, Apis mellifera. Kurshan PT, Hamilton IS, Mustard JA, Mercer AR. J Comp Neurol. 2003 Nov 3;466(1):91-103.