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Role of NMDA receptor dysfunction in epileptic disorders
NMDA receptors are key mediators of brain plasticity, converting neuronal activity into long-term changes in synaptic structure and function. Mutations affecting the GluN2A subunit have recently been identified in focal childhood epilepsies ranging from mild, self-limiting rolandic epilepsy to severe epileptic encephalopathies (Lemke et al 2013, Nat Genet 45:1067-1072). By contrast, defects in GluN2B subunit have been linked to West syndrome, intellectual disability, autism and schizophrenia (Lemke et al 2014, Ann Neurol 75:147-154). We aim to understand how different mutations in GluN2A and GluN2B cause such a wide spectrum of neurological disorders, defining pathogenic mechanisms, exploring new therapeutic avenues and generating new acute mouse models of NMDA receptor dysfunction. Future research aims to: (i) Use molecular biology to generate a series of GluN2A and GluN2B missense mutants for analysis in cellular trafficking assays. We will also use molecular modelling to predict potential pathogenic impacts of missense changes. These approaches will enable us to prioritise GluN2A and GluN2B mutations for ii) detailed electrophysiological analysis, which will examine changes in agonist binding, modulation by Zn2+, voltage-sensitive Mg2+ blockade, and changes to kinetics of NMDA currents; (iii) To explore the possibility of developing new treatments for epilepsy, by testing the efficacy of NMDA receptor antagonists on mutant NMDARs; iv) To generate and characterise novel gain-of-function knock-in mouse models for GluN2A and GluN2B dysfunction that are defective in voltage-dependent Mg2+ blockade. Key collaborators include: Saskia Biskup (Center for Genomics and Transcriptomics, Tuebingen, Germany), Kirsten Harvey (UCL School of Pharmacy), Manju Kurian (UCL Institute of Child Health), Johannes Lemke (Institut f├╝r Humangenetik, Universit├Ątsklinikum Leipzig, Germany), Trevor Smart (UCL NPP).
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