UCSF

The remarkable ability of the brain to interpret vast amounts of stimuli and adapt to new situations is dependent upon not only the proper formation, but also the functional specialization of synaptic connections between neurons. On the molecular level, we are just beginning to understand the networks that regulate synapse development, termed synaptic organizing complexes. Recent work has identified a number of different proteins required for the formation of synapses, i.e. synaptogenesis. However, much less is understood about the protein networks that guide the maintenance and maturation of these nascent synapses. Here, I describe a novel synaptic organizing complex comprised of the secreted protein LGI1 and its transmembrane partners, ADAM22 and ADAM23. I present data demonstrating that LGI1 mediates a transsynaptic complex, including pre- and postsynaptic ADAMs and members of the MAGUK family of intracellular scaffolding proteins. I go on to characterize the functional impact of this transsynaptic complex, revealing that ADAM22 and ADAM23 are essential to maintaining excitatory synapses, and that LGI1 acts as a paracrine signal originating from axons and dendrites to modulate the strength of these synapses. Finally, I address the function of the AMPAR-interacting protein SynDIG1 in synaptic organization, and show that, despite its previous implication in synaptic maturation and possible role as an AMPAR auxiliary subunit, it is specifically a synaptogenic molecule at excitatory synapses.