NMDA receptors in neurodevelopment and seizure pathogenesis

ABSTRACT Neurodevelopmental disorders, including epilepsy and seizure disorders, are one of the most common di- agnoses in pediatric patients. Often, genes implicated in these disorders encode proteins that play a role in both neurodevelopment and synaptic transmission. However, whether disease pathologies arise due to a neurodevelopmental change, a change in synaptic signaling, or both is generally unknown. NMDA receptors (NMDARs) are glutamate-gated ion channels that contribute to neurodevelopment in addition to their clas- sical role in excitatory neurotransmission. Neurodevelopmental disorders, including seizure disorders, are common in patients with disease-associated variants (DAVs) in the GRIN genes that encode NMDAR sub- units. Indeed, patients with DAVs in GRIN1, encoding the obligatory GluN1 subunit, and GRIN2A, encoding GluN2A, often present with seizures. Notably, previous work from the Wollmuth and Sirotkin Labs has shown that the absence of NMDARs leads to decreased expression of the Cl- transporter KCC2, a marker of neu- ronal maturation necessary for inhibitory GABAergic signaling. Likewise, in a rodent model, the absence of Grin2a coincides with delayed maturation of GABAergic interneurons, suggesting a neurodevelopmental role that may be specific to GluN2A-containg NMDARs. Based on these observations, my central hypoth- esis is that the loss-of-function of GRIN1 or GRIN2A alters neurotypical brain activity, leading to a pro- excitatory state, due to a putative delay in neuronal maturation. To test this hypothesis, I will use zebrafish to model the loss-of-function of grin1 or grin2A and an array of techniques including behavioral analyses, whole-brain imaging, and electrophysiology. Initially (Aim 1), I will define the role of the loss-of-function of grin1 and grin2A in whole-brain activity, specifically in the context of seizures. Subsequently (Aim 2), I will address the extent to which neural circuit formation is impacted. Finally (Aim 3), I will directly address how loss-of-function impacts synaptic transmission. This work will provide new insights into NMDAR-associated seizure activity and potential therapeutic targets for the treatment of seizures in pediatric patients.