A Shared Synaptic Defect in Autism-Linked Neuroligin-3 Mutations

Földy C, Malenka RC, Südhof TC. Autism-associated neuroligin-3 mutations commonly disrupt tonic endocannabinoid signaling. Neuron 2013;78(3):498-509. doi: 10.1016/j.neuron.2013.02.036.

Background: Neuroligins are postsynaptic adhesion molecules that organize synaptic structure and function by interacting with presynaptic neurexins. Mutations in the neuroligin-3 (NL3) gene, including the R451C substitution and NL3 deletion, have been linked to autism spectrum disorders. Previous studies found robust synaptic alterations in R451C knockin mice but minimal effects in NL3 knockouts, raising uncertainty about a shared mechanism underlying autism-associated NL3 mutations.

Hypothesis: This study hypothesized that both NL3 R451C and NL3 knockout mutations produce a common synaptic defect that could reveal a shared molecular mechanism relevant to autism pathogenesis.

Methods: The authors performed paired whole-cell recordings between identified hippocampal interneurons and pyramidal neurons in mouse brain slices to assess GABAergic synaptic transmission. They compared synapses formed by parvalbumin (PV) and cholecystokinin (CCK) basket cells in wild-type, NL3 R451C knockin, and NL3 knockout mice. Morphological reconstructions of biocytin-filled neurons were performed using Neurolucida to assess axonal and dendritic organization.

Results: The R451C mutation markedly reduced synaptic strength at PV basket cell synapses but enhanced transmission at CCK basket cell synapses. The NL3 knockout produced no change at PV synapses but mimicked the R451C enhancement at CCK synapses. Both mutations abolished tonic, but not phasic, endocannabinoid signaling that normally suppresses GABA release from CCK basket cells. Modeling and simulation confirmed altered presynaptic release probabilities without structural changes.

Conclusions: The study concludes that NL3 is essential for tonic endocannabinoid signaling but not for phasic signaling. Both NL3 R451C and knockout mutations disrupt this mechanism, suggesting that impaired tonic endocannabinoid modulation of inhibition may contribute to autism pathophysiology.