NMDA receptors (NMDARs) are glutamate-gated ion channels that mediate excitatory neurotransmission in the brain. Many higher order neural processes including synaptogenesis and the synaptic plasticity underlining learning and memory depend on NMDAR-mediated transmission. The NMDAR GluN2B subunit is critically involved in early brain development. Accordingly, missense and nonsense mutations in GRIN2B, the gene encoding GluN2B, are associated with autism spectrum disorder, intellectual disability, and schizophrenia among other neurodevelopmental disorders. The specific role of GluN2B in brain development and the causal link between GluN2B dysfunction and these diverse disorders is unknown. Our goal, taking advantage of the power of zebrafish, is to identify the role of GluN2B in brain development and neurodevelopmental disorders and to pioneer new therapies to treat such disorders. We must first establish the use of zebrafish as a model system to study GluN2B in neurodevelopmental disorders. To do so, we will test whether zebrafish GluN2B (zGluN2B) functions similarly to human GluN2B and if it displays a comparable pharmacology (Aim#1). In addition, we need to identify GluN2B-dependent zebrafish behaviors (Aim#2), which provide a pathway to study circuit development and a substrate for behaviorally-based drug screens.
In Aim 1, we will use heterologous expression zebrafish and human NMDAR subunits in HEK293 cells and patch clamp electrophysiology to characterize functional and pharmacological properties.
In Aim 2, we will examine how knockout of zebrafish GluN2B affects behaviors associated with human neurodevelopmental disorders. In the long-term, zebrafish have the potential to provide a platform to study the role of GluN2B in brain development and the effects of human GRIN2B missense mutations on neural circuit development and carry out behaviorally based high throughput small molecule drug screens to counter the effects of GluN2B dysfunction.
Neurodevelopmental disorders including autism spectrum disorder, intellectual disability, and schizophrenia have devasting impacts on families. The etiology of neurodevelopmental disorders is poorly defined, limiting treatment alternatives. The GluN2B subunit of the NMDA receptor is a critical element in normal brain development and when dysfunctional leads to numerous neurodevelopmental disorders. We are studying how the GluN2B subunit contributes to brain development with the long-term goal of developing novel treatments.
