title: Pathogenic mechanism of an autism-associated neuroligin mutation involves altered AMPA-receptor trafficking.
abstract: Neuroligins are postsynaptic cell-adhesion molecules that bind to presynaptic neurexins. Although the general synaptic role of neuroligins is undisputed, their specific functions at a synapse remain unclear, even controversial. Moreover, many neuroligin gene mutations were associated with autism, but the pathophysiological relevance of these mutations is often unknown, and their mechanisms of action uninvestigated. Here, we examine the synaptic effects of an autism-associated neuroligin-4 substitution (called R704C), which mutates a cytoplasmic arginine residue that is conserved in all neuroligins. We show that the R704C mutation, when introduced into neuroligin-3, enhances the interaction between neuroligin-3 and AMPA receptors, increases AMPA-receptor internalization and decreases postsynaptic AMPA-receptor levels. When introduced into neuroligin-4, conversely, the R704C mutation unexpectedly elevated AMPA-receptor-mediated synaptic responses. These results suggest a general functional link between neuroligins and AMPA receptors, indicate that both neuroligin-3 and -4 act at excitatory synapses but perform surprisingly distinct functions, and demonstrate that the R704C mutation significantly impairs the normal function of neuroligin-4, thereby validating its pathogenicity.
authors.affiliation: Department of Molecular and Cellular Physiology and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA.|Institute for Stem Cell Biology and Regenerative Medicine and Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Chanda
authors.affiliation: Department of Molecular and Cellular Physiology and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Aoto
authors.affiliation: Department of Molecular and Cellular Physiology and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: S-J
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine and Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Wernig
authors.affiliation: Department of Molecular and Cellular Physiology and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: T C
authors.initials: TC
authors.lastname: Südhof
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000235:genetics*; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics*; D018929:Cell Culture Techniques; D006624:Hippocampus / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics*; D008815:Mice, Inbred Strains; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000378:metabolism; D009830:Olfactory Bulb / Q000378:metabolism; D018091:Receptors, AMPA / Q000378:metabolism; D013569:Synapses / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D008565:Membrane Proteins; C430845:NLGN4X protein, human; D009419:Nerve Tissue Proteins; D018091:Receptors, AMPA; C098004:neuroligin 3; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid