GluN2D in Development and Disease

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PROJECT SUMMARY/ABSTRACT NMDA receptors (NMDARs) are ligand-gated ion channels that are activated by glutamate, the principle excitatory neurotransmitter of the brain. Missense mutations in NMDAR subunits are associated with multiple neurodevelopmental disorders including autism, epilepsy and morphological anomalies. Nevertheless, it is unclear how particular functional alterations produce disease, especially as both gain and loss of function alleles have been identified with the same disorders. This proposal uses zebrafish as a model to explore the developmental roles of the understudied GluN2D subunit, which is associated with a severe neurological disorder, Developmental and Epileptic Encephalopathy (DEE). Based on novel preliminary data that shows NMDARs repress forebrain neurogenesis, we hypothesize that GluN2D dysfunction alters early neurogenesis and the subsequent balance of excitatory and inhibitory neurons. We propose two aims to test this premise. In Aim 1 we will determine the effects of complete loss of GluN2D on neurogenesis to establish a foundation for understanding the pathogenic impacts of GluN2D disease variants. In Aim 2 we will generate zebrafish models harboring DEE-associated GluN2D variants to directly assess their effects on neurogenesis. This work will provide new insights into the role of GluN2D in early development and establish a scalable strategy to interrogate the pathogenic mechanisms produced disease associated NMDAR variants that result in autism, epilepsy, and other neurodevelopmental disorders.