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.
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We thank Drs Sungjin Lee and Salome Botelho for the help of Cbln1 purification and RT-PCR, and members of the Südhof labs for valuable discussions. This study was supported by a grant from the Simons Foundation Autism Research Initiative (307762, to TCS) and from NIMH (R37MH052804, to TCS). Correspondence and requests for materials should be addressed to BZ (email@example.com).
The authors declare no conflict of interest.
Supplementary Information accompanies the paper on the Molecular Psychiatry website
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Zhang, B., Seigneur, E., Wei, P. et al. Developmental plasticity shapes synaptic phenotypes of autism-associated neuroligin-3 mutations in the calyx of Held. Mol Psychiatry 22, 1483–1491 (2017) doi:10.1038/mp.2016.157
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