Jaewon Ko is interested in how synapses form and function during development and in adulthood. His work focuses on (1) the role of synaptic cell-adhesion molecules in shaping synapse properties, (2) pre- and postsynaptic mechanisms of synaptic development, and (3) impairments in synapse formation and function in neuropsychiatric disorders. To address these questions, the Ko laboratory employs multiple, interdisciplinary approaches ranging from biochemical and biophysical studies to physiological and behavioral analyses of mutant mice deficient in key synaptic adhesion molecules and their associated proteins. The Ko laboratory is currently working on problems related to social cognitive processes at synaptic and circuit levels.
Neurons communicate with each other through synaptic transmission at specialized intercellular junctions called ‘synapses’. Synapses form not only during development, but also throughout life. Synapses transmit, process, and store information in the brain. During synaptic transmission, a presynaptic neuron releases a chemical neurotransmitter that is recognized by the postsynaptic neuron. Neurotransmitter release is triggered when an action potential opens voltage-gated calcium channels and calcium flows into the presynaptic nerve terminal. Released neurotransmitters elicit a postsynaptic response by binding to specific postsynaptic receptors. Work in Jaewon Ko’s laboratory addresses three fundamental sets of questions about how synapses form and function: (1) how does a presynaptic nerve terminal form a synapse on a postsynaptic neuron in the first place; (2) how are the properties of the resulting synapses specified; and (3) how are synapses impaired in neuropsychiatric disorders? The overall goal is to describe the principal molecular mechanisms underlying these processes; that is, to identify the molecules involved, delineate their properties and structures, and understand their physiological functions. Two major research projects are ongoing in the laboratory.
1. Synapse formation and function by key synaptic cell-adhesion molecules
At a synapse, pre- and postsynaptic compartments are linked by trans-synaptic cell-adhesion molecules that, in turn, are coupled to the presynaptic release machinery or postsynaptic receptors. Synaptic cell-adhesion molecules (CAMs) function in various stages of synaptogenesis – the process of synapse creation – encompassing synapse formation, maturation, refinement, plasticity, and elimination. We are currently focusing on a subset of the known synaptic CAMs, primarily LRRTMs, Slitrks, LAR-RPTPs, MDGAs and calsyntenins; however, their synaptic functions have only recently begun to come into focus (Ko et al., 2009a; Ko et al., 2009b; Ko et al., 2011; Ko, 2012; Yim et al., 2013; Um & Ko, 2013; Um et al., 2014; Ko et al., 2015a; Han et al., 2016). LRRTMs (leucine-rich repeat transmembrane proteins) and Slitrks (Slit and Trk-like family) contain leucine-rich repeats (LRRs) that function as protein-protein interaction domains (Figure 1) and govern the distinct types of synapse development and function (i.e., LRRTMs, Slitrk1, Slitrk2, Slitrk4 and Slitrk5 in excitatory synapses vs. Slitrk3 in inhibitory synapses). Intriguingly, LAR-RPTPs function in concert with Slitrks in an isoform-dependent manner (Um & Ko, 2013). Calsyntenins, evolutionarily conserved postsynaptic CAMs, dictate inhibitory synapse development and function, partly in conjunction with presynaptic neurexins. Researchers in the Ko laboratory are interested in exploring the synaptic functions of a series of these synaptic CAMs in cultured neurons and transgenic mice (Ko et al., 2015b).
2. Synapse formation and function by synaptic cell adhesion-associated scaffolds
For synaptic CAMs to exert biological effects in neurons, signals generated by their physical and chemical attachment must be intracellularly transduced to each compartment. Major scaffolding proteins have been identified and shown to interact with synaptic CAMs; for example, the important post-synaptic density protein PSD-95 interacts with neuroligins, LRRTMs, netrin-G ligands, and SALMs (synaptic cell adhesion-like molecules). However, it remains unclear how signals generated by the unique pairings of synaptic adhesion molecules affect intracellular signal transduction pathways; clarifying this issue is crucial for understanding how synaptic CAMs act independently and collaboratively to maintain/regulate the structure and function of synapses. The Ko laboratory is interested in discovering novel scaffolds that interact with key synaptic CAMs and deciphering the detailed flow of intracellular signals in both pre- and postsynaptic neurons. On a larger scale, a major challenge in the field is to understand how these synaptic CAMs shape neural circuits and collaborate with other trans-synaptic CAMs. An even more important and broader question is how synapses form in the first place and what additional molecules shape their properties. Ko laboratory researchers have recently made the interesting observation that members of the glycosylphatidylinositol (GPI)-anchored protein family (MDGAs) directly interact with and alter the cell-adhesion properties of neuroligin-2 to regulate inhibitory synapse development and function (Lee et al., 2013). In general, how neural circuits are established and how key synaptic CAMs contribute to their formation are among the major questions of modern neuroscience. The molecular components involved are only now beginning to be identified; undoubtedly many additional synaptic CAMs will ultimately be implicated. Given the complexity of synaptic connectivity (at least 1016 synapses exist in the human brain), a combinatorial code—possibly one based on rather simple principles—may apply. Unraveling this code, which will almost certainly involve a major role for key synaptic CAMs as central trans-synaptic organizers, would significantly advance the molecular neuroscience field. Addressing these questions is the major theme of the Ko laboratory’s current research.
Ko J, Zhang C, Arac D, Boucard AA, Brunger AT and Südhof TC (2009a). “Neuroligin-1 performs neurexin-dependent and neurexin-independent functions in synapse validation”. EMBO J 28:3244-3255.
Ko J, Fuccillo MV, Malenka RC and Südhof TC (2009b). “LRRTM2 Functions as a Neurexin Ligand in Promoting Excitatory Synapse Formation”. Neuron 64: 791-798.
Ko J, Soler-Llavina G, Fuccillo MV, Malenka RC and Südhof TC (2011). “Neuroligin/LRRTM prevent Ca2+- and activity-dependent synapse elimination in cultured neurons” J Cell Biol 194: 323-334.
Ko J (2012). “Leucine-rich repeat superfamily of synaptic adhesion molecules: LRRTMs and Slitrks” Mol Cell 34: 335-340.
Ko JS, Pramanik G, Um JW, Shim JS, Lee D, Kim KH, Chung GY, Condomitti G, Kim HM, Kim H, de Wit J, Park KS, Tabuchi K and Ko J (2015a). “PTPsigma functions as a presynaptic receptor for the glypican-4/LRRTM4 complex and is essential for excitatory synaptic transmission” Proc Natl Acad Sci USA 112: 1874-1879.
Ko J, Choii G and Um JW (2015b). “The balancing act of GABAergic synapse organizers” Trends Mol Med 21: 256-268.
Lee K, Kim Y, Lee SJ, Qing Y, Lee D, Lee HW, Kim H, Je HS, Südhof TC and Ko J (2013). “MDGAs interact selectively with neuroligin-2 but not other neuroligins to regulate inhibitory synapse development” Proc Natl Acad Sci USA 110: 336-340.
Han KA, Jeon S, Um JW and Ko J (2016). “Emergent Synapse Organizers: LAR-RPTPs and Their Companions” Int Rev Cell Mol Biol 324: 39-65.
Yim YS, Kwon Y, Nam J, Yoon HI, Lee K, Kim DG, Kim E, Kim CH and Ko J (2013). “Slitrks control excitatory and inhibitory synapse formation with LAR receptor protein tyrosine phosphatases” Proc Natl Acad Sci USA 110: 4057-4062
Um JW and Ko J (2013). “LAR-RPTPs: synaptic adhesion molecules that shape synapse development” Trends Cell Biol 23: 465-475
Um JW, Pramanik G, Ko JS, Song MY, Lee D, Kim H, Park KS, Südhof TC, Tabuchi K and Ko J (2014). “Calsyntenins function as synaptogenic adhesion molecules in concert with neurexinst” Cell Rep 6: 1096-1109