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Autism-associated neuroligin-3 mutations commonly disrupt tonic endocannabinoid signaling.

Neuron | 2013

Neuroligins are postsynaptic cell-adhesion molecules that interact with presynaptic neurexins. Rare mutations in neuroligins and neurexins predispose to autism, including a neuroligin-3 amino acid substitution (R451C) and a neuroligin-3 deletion. Previous analyses showed that neuroligin-3 R451C-knockin mice exhibit robust synaptic phenotypes but failed to uncover major changes in neuroligin-3 knockout mice, questioning the notion that a common synaptic mechanism mediates autism pathogenesis in patients with these mutations. Here, we used paired recordings in mice carrying these mutations to measure synaptic transmission at GABAergic synapses formed by hippocampal parvalbumin- and cholecystokinin-expressing basket cells onto pyramidal neurons. We demonstrate that in addition to unique gain-of-function effects produced by the neuroligin-3 R451C-knockin but not the neuroligin-3 knockout mutation, both mutations dramatically impaired tonic but not phasic endocannabinoid signaling. Our data thus suggest that neuroligin-3 is specifically required for tonic endocannabinoid signaling, raising the possibility that alterations in endocannabinoid signaling may contribute to autism pathophysiology.

Pubmed ID: 23583622 RIS Download

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Associated grants

  • Agency: NIDA NIH HHS, United States
    Id: K99DA034029
  • Agency: NINDS NIH HHS, United States
    Id: NS069375
  • Agency: NIMH NIH HHS, United States
    Id: P50 MH086403
  • Agency: Howard Hughes Medical Institute, United States
  • Agency: NIDA NIH HHS, United States
    Id: R01 DA030379
  • Agency: NIDA NIH HHS, United States
    Id: K99 DA034029
  • Agency: NINDS NIH HHS, United States
    Id: P30 NS069375

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RRID:SCR_001775

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NeuroExplorer (tool)

RRID:SCR_001818

Data analysis software for neurophysiology with a multitude of features, including: * Import of native data files created by many popular data acquisition systems * All standard histogram and raster analyses * Shift predictors in crosscorrelograms and color markers in perievent rasters * Joint PSTH, burst analysis and many more analyses of timestamped data * Spectral analysis of spike and continuous data * 3D data view and animation * Fully customizable WYSIWYG graphics * Custom analysis and batch mode processing with internal scripting language * Direct data link to Matlab and Excel * Statistical tests via direct link to R-project

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