Cooperative Action of Neuroligins and Brain-Derived Neurotrophic Factor Mediates Presynaptic Maturation

Mutations in genes for postsynaptic cell adhesion molecules called neuroligins – in particular the isoforms neuroligin-1, neuroligin-3, and neuroligin-4 – have been implicated in autism spectrum disorders. In cultured neurons, neuroligin-1 mediates structural and functional maturation of presynaptic terminals. What still remains untested, however, are the transsynaptic signals that allow neuroligins, being postsynaptic, to regulate presynaptic maturation. So far, it has been expected that the interaction of neuroligins and their presynaptic partners, the neurexins, is involved. However, the precise mechanism has not been established. Brain-derived neurotrophic factor is an activity-dependent secreted molecule that has been implicated in many mental disorders, including autism spectrum disorders. It has been shown to support the survival and differentiation of neurons, induce synapse formation and maturation, and modulate synaptic transmission. Here, I introduce brain-derived neurotrophic factor as a potential mediator of neuroligin-induced presynaptic maturation. I found that brain-derived neurotrophic factor, neuroligin-1, and neuroligin-2 display similar properties in regard to inducing presynaptic maturation. By perturbing brain-derived neurotrophic factor signaling, I discovered that it is required for neuroligin-induced presynaptic maturation and that specifically postsynaptic brain-derived neurotrophic factor is required for neuroligin-1-induced presynaptic maturation. Remarkably, application of brain-derived neurotrophic factor was able to restore impaired presynaptic maturation in cultures from neuroligin-1 knock-out mice. Taken together, my results show that neuroligins and brain-derived neurotrophic factor act in the same pathway to induce presynaptic maturation. The ability of brain-derived neurotrophic factor to rescue defective maturation in neuroligin-1 knock-out animals could provide a potential therapeutic target for autism spectrum disorders.2022-09-2