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

ABSTRACT: 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.

SUBMITTER: Zhang B

PROVIDER: S-EPMC5687809 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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

Zhang B B Seigneur E E Wei P P Gokce O O Morgan J J Südhof T C TC

Molecular psychiatry 20161011 10

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 transmissio ...[more]

PMID: 27725662

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Project description:α-Synuclein is a presynaptic protein the function of which has yet to be identified, but its neuronal content increases in patients of synucleinopathies including Parkinson's disease. Chronic overexpression of α-synuclein reportedly expresses various phenotypes of synaptic dysfunction, but the primary target of its toxicity has not been determined. To investigate this, we acutely loaded human recombinant α-synuclein or its pathological mutants in their monomeric forms into the calyces of Held presynaptic terminals in slices from auditorily mature and immature rats of either sex. Membrane capacitance measurements revealed significant and specific inhibitory effects of WT monomeric α-synuclein on vesicle endocytosis throughout development. However, the α-synuclein A53T mutant affected vesicle endocytosis only at immature calyces, whereas the A30P mutant had no effect throughout. The endocytic impairment by WT α-synuclein was rescued by intraterminal coloading of the microtubule (MT) polymerization blocker nocodazole. Furthermore, it was reversibly rescued by presynaptically loaded photostatin-1, a photoswitcheable inhibitor of MT polymerization, in a light-wavelength-dependent manner. In contrast, endocytic inhibition by the A53T mutant at immature calyces was not rescued by nocodazole. Functionally, presynaptically loaded WT α-synuclein had no effect on basal synaptic transmission evoked at a low frequency, but significantly attenuated exocytosis and impaired the fidelity of neurotransmission during prolonged high-frequency stimulation. We conclude that monomeric WT α-synuclein primarily inhibits vesicle endocytosis via MT overassembly, thereby impairing high-frequency neurotransmission.SIGNIFICANCE STATEMENT Abnormal α-synuclein abundance is associated with synucleinopathies including Parkinson's disease, but neither the primary target of α-synuclein toxicity nor its mechanism is identified. Here, we loaded monomeric α-synuclein directly into mammalian glutamatergic nerve terminals and found that it primarily inhibits vesicle endocytosis and subsequently impairs exocytosis and neurotransmission fidelity during prolonged high-frequency stimulation. Such α-synuclein toxicity could be rescued by blocking microtubule polymerization, suggesting that microtubule overassembly underlies the toxicity of acutely elevated α-synuclein in the nerve terminal.

Dataset Information

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

Publications

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

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