Potential Therapeutic Target to Treat Autism

A study in The Journal of Cell Biology reveals that a neuronal protein linked to neurodevelopmental disorders restrains the development of inhibitory synapses. MDGA1 disrupts the interaction between neuroligin-2 and neurexin-1, two synaptic cell adhesion molecules associated with autism that promote inhibitory synapse development

Synapse development is promoted by a range of cell adhesion molecules that join neurons and organize synaptic proteins. Many of these adhesion molecules are linked to neurodevelopmental disorders; mutations in neuroligin and neurexin proteins, are associated with autism. Other groups of proteins linked to these disorders regulates the function of neuroligins and neurexins in order to suppress the development of inhibitory synapses.

Ann Marie Craig and researchers from theUniversityofBritish Columbiainvestigated the function of MDGAs using co-culture assays, in which postsynaptic proteins like neuroligin-1 or -2 are expressed in non-neuronal cells and then tested for their ability to induce presynaptic differentiation in neighboring neurons. The researchers found that MDGA1’s extracellular domains bound to neuroligin-2, blocking its association with neurexin. “Overexpressing MDGA1 in neurons reduced the density of inhibitory synapses without affecting excitatory synapses,” Craig says. Knocking down MDGA1, on the other hand, increased inhibitory synapse development but had no effect on excitatory synapses.

“I can’t think of any other proteins that specifically suppress inhibitory synapse formation,” says Craig. Indeed, very few proteins in general have been identified as negative regulators of synapse development, compared to the many proteins that are known to promote synaptogenesis. The results suggest that function-altering mutations in the MDGA proteins may disrupt the balance of excitatory and inhibitory synapses in the brain, potentially explaining the development of autism and other neurodevelopmental disorders.

“This puts MDGAs in the same pathway as neurexins and neuroligins and strengthens the evidence for the involvement of synaptic organizing proteins in autism and schizophrenia,” Craig explains.

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