Atypical neuronal communication mechanisms disrupted in neurodevelopmental disease
The diversity of neurodevelopmental and neuropsychiatric disease can be commonly unified by fundamental deficits in neuronal communication, particularly at the interface between neurons known as the synapse. Nevertheless, the molecular components facilitating these critical neuronal communication networks remain to be fully elucidated. Previously, we understood that neuronal communication mechanisms heavily relied on chemical receptors: known for receiving and interpreting chemical messages from communicating neurons. Because of this important role, these receptors have become hotspots for therapeutic drug design for neurodevelopmental and neuropsychiatric disease and have demonstrated encouraging potential.
Excitingly, we’ve now discovered that these same receptors are participating in additional atypical neuronal communication pathways that were previously undescribed, yet appear to be disrupted in patients with diverse neurodevelopmental and neuropsychiatric disease. Notably, what were once described as scaffolding molecules, providing structural connections between neurons, are now being revealed to alter how receptors receive and interpret chemical messages, ultimately advancing our understanding of neuronal communication. Most excitingly, preliminary data suggests these receptors may in turn reciprocate communication to scaffolding molecules, thereby providing atypical neuronal communication pathways that have previously been
This proposal will focus on a relatively understudied gene encoding a scaffolding molecule at the synapse highly associated with neurodevelopmental disease. Many patients with mutations in this gene have presented with diverse neurodevelopmental deficits. The consequences of these disease-causing mutations include complete lack of scaffolding molecule, mutation to the interface between these molecules and receptors, and mutation of previously undescribed region that we believe facilitates atypical neuronal communication. Using human cell lines, we will recapitulate these disease-causing mutations at a cellular level and evaluate the consequence on typical and novel, atypical communication networks: with the ultimate goal of guiding better early intervention and treatment options for patients with neurodevelopmental disease harbouring these mutations.
Henry Dunn , University of Manitoba
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