Developmental plasticity shapes synaptic phenotypes of autism-associated neuroligin-3 mutations in the calyx of Held

• Published in: Molecular psychiatry 2017-10, Vol.22 (10), p.1483-1491
• Main Authors: Zhang, B, Seigneur, E, Wei, P, Gokce, O, Morgan, J, Südhof, T C
• Format: Article
• Language: English
• Subjects: 692/699/476/1373; Animals; Autism; Autistic Disorder - genetics; Autistic Disorder - metabolism; Behavioral Sciences; Biological Psychology; Cell adhesion molecules; Cell Adhesion Molecules, Neuronal - genetics; Cell Adhesion Molecules, Neuronal - metabolism; Developmental plasticity; Disease Models, Animal; Gene Knock-In Techniques; Gene mutation; Genetic aspects; Hippocampus - metabolism; Medicine; Medicine & Public Health; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mental disorders; Mice; Mice, Knockout; Mimicry; Mutation; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neuronal Plasticity - genetics; Neurons - metabolism; Neurosciences; original-article; Pharmacotherapy; Phenotypes; Phenotypic plasticity; Plastic properties; Plasticity; Psychiatry; Retina; Synapses; Synapses - metabolism; Synapses - physiology; Synaptic plasticity; Synaptic Transmission; Synaptogenesis; Trapezoid Body - metabolism; Trapezoid Body - physiology
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/mp.2016.157

Neuroligins are postsynaptic cell-adhesion molecules that bind to presynaptic neurexins. Mutations in neuroligin-3 predispose to autism, but how such mutations affect synaptic function remains incompletely understood. Here we systematically examined the effect of three autism-associated mutations, the neuroligin-3 knockout, the R451C knockin, and the R704C knockin, on synaptic transmission in the calyx of Held, a central synapse ideally suited for high-resolution analyses of synaptic transmission. Surprisingly, germline knockout of neuroligin-3 did not alter synaptic transmission, whereas the neuroligin-3 R451C and R704C knockins decreased and increased, respectively, synaptic transmission. These puzzling results prompted us to ask whether neuroligin-3 mutant phenotypes may be reshaped by developmental plasticity. Indeed, conditional knockout of neuroligin-3 during late development produced a marked synaptic phenotype, whereas conditional knockout of neuroligin-3 during early development caused no detectable effect, mimicking the germline knockout. In canvassing potentially redundant candidate genes, we identified developmentally early expression of another synaptic neurexin ligand, cerebellin-1. Strikingly, developmentally early conditional knockout of cerebellin-1 only modestly impaired synaptic transmission, whereas in contrast to the individual single knockouts, developmentally early conditional double knockout of both cerebellin-1 and neuroligin-3 severely decreased synaptic transmission. Our data suggest an unanticipated mechanism of developmental compensation whereby cerebellin-1 and neuroligin-3 functionally occlude each other during development of calyx synapses. Thus, although acute manipulations more likely reveal basic gene functions, developmental plasticity can be a major factor in shaping the overall phenotypes of genetic neuropsychiatric disorders.