title: The LGI1-ADAM22 protein complex directs synapse maturation through regulation of PSD-95 function.
abstract: Synapse development is coordinated by a number of transmembrane and secreted proteins that come together to form synaptic organizing complexes. Whereas a variety of synaptogenic proteins have been characterized, much less is understood about the molecular networks that support the maintenance and functional maturation of nascent synapses. Here, we demonstrate that leucine-rich, glioma-inactivated protein 1 (LGI1), a secreted protein previously shown to modulate synaptic AMPA receptors, is a paracrine signal released from pre- and postsynaptic neurons that acts specifically through a disintegrin and metalloproteinase protein 22 (ADAM22) to set postsynaptic strength. We go on to describe a novel role for ADAM22 in maintaining excitatory synapses through PSD-95/Dlg1/zo-1 (PDZ) domain interactions. Finally, we show that in the absence of LGI1, the mature synapse scaffolding protein PSD-95, but not the immature synapse scaffolding protein SAP102, is unable to modulate synaptic transmission. These results indicate that LGI1 and ADAM22 form an essential synaptic organizing complex that coordinates the maturation of excitatory synapses by regulating the functional incorporation of PSD-95.
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158; Neuroscience Graduate Program, University of California, San Francisco, CA 94158;
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Lovero
authors.affiliation: Division of Membrane Physiology, Department of Cell Physiology, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Aichi 444-8787, Japan; Department of Physiological Sciences, School of Life Science, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Aichi 444-8787, Japan;
authors.forename: Yuko
authors.initials: Y
authors.lastname: Fukata
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158; Neuroscience Graduate Program, University of California, San Francisco, CA 94158;
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Granger
authors.affiliation: Division of Membrane Physiology, Department of Cell Physiology, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Aichi 444-8787, Japan; Department of Physiological Sciences, School of Life Science, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Aichi 444-8787, Japan;
authors.forename: Masaki
authors.initials: M
authors.lastname: Fukata
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158; Department of Physiology, University of California, San Francisco, CA 94158 nicoll@cmp.ucsf.edu.
authors.forename: Roger A
authors.initials: RA
authors.lastname: Nicoll
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D020816:Amino Acid Motifs; D000818:Animals; D001921:Brain / Q000473:pathology; D002462:Cell Membrane / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D004566:Electrodes; D005786:Gene Expression Regulation; D051528:Guanylate Kinases / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D010641:Phenotype; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000378:metabolism*; D013569:Synapses / Q000502:physiology*; D009435:Synaptic Transmission
chemical_list: D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; C492120:Lgi1 protein, mouse; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011506:Proteins; D051528:Guanylate Kinases; D051722:ADAM Proteins; C121258:Adam22 protein, mouse
keywords: ADAM22; LGI1; PSD-95; synapse development; synaptic organization