Researchers have identified altered endocannabinoid signaling as a common mechanism by which different mutations in the gene that encodes the synaptic protein neuroligin-3 could cause autism (Neuron 78, 498–509).

Credit: Ramon Andrade/Science Source

Several mutations in the gene that encodes neuroligin-3 have been linked to autism, including a deletion mutation and a substitution at amino acid 451 of the protein. Csaba Földy et al. examined the electrophysiological properties of synapses from inhibitory interneurons onto pyramidal neurons in the hippocampus with the goal of identifying synaptic dysfunction that would be commonly induced by both the mutations, possibly leading to autism. The researchers found that inhibitory neurotransmission from cholecystokinin-positive interneurons was enhanced in brain slices from mice with either mutation, whereas this was not the case with parvalbumin-positive interneurons.

Cholecystokinin interneurons express cannabinoid receptors, and deficits in cannabinoid signaling can enhance inhibitory neurotransmission. Földy et al. found that a cannabinoid receptor antagonist could enhance inhibitory neurotransmission in brain slices from wild-type mice, but could not do so in brain slices from either of the neuroligin-3–mutant mice, suggesting that they both had deficits in endocannabinoid signaling. How this mechanism could lead to the behavioral phenotypes associated with autism remains to be explored.