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.