The role of NMDA receptor dysfunction in epileptic disorders

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The central nervous system is an intricate network of nerve cells that transmit and receive messages. This communication occurs mostly at specialised sites of contact known as synapses found all over the surface of neurons, but typically on fine neuronal processes known as dendrites. At these sites, an arriving nerve impulse causes the release of a chemical neurotransmitter from the 'presynaptic' cell, which then interacts with protein receptor molecules in the cell membrane of a neighbouring 'postsynaptic' nerve cell. We aim to study receptors activated by two neurotransmitters, glutamate and glycine, which are classified as excitatory NMDA receptors, based on selectivity for an artificial toxin N-methyl-D-aspartate. NMDA enhances nerve cell excitability by enabling a flow of ions via an integral ion channel. The opening of these receptors alters the electrical state of the cell, either transmitting or subtly altering incoming nerve impulses. NMDA receptors are important for normal function of synapses and processes involved in learning and memory. Dysfunction of NMDA receptors has previously been implicated in neurodegeneration, pain, stroke and schizophrenia. Drugs targeting NMDA receptors have also shown clinical promise in indications such as Alzheimer's disease, Parkinson's disease, pain and depression. Recent studies involving the applicants and other researchers world-wide have shown that genetic defects in genes encoding NMDA receptor subunits cause different types of childhood epilepsy, intellectual disability, autism and schizophrenia. Initial results suggest that several of the genetic changes identified in these children appear to cause over-excitation via NMDA receptors. Our project aims to understand how such changes in NMDA receptor genes can cause such a wide range of neurological disorders. We aim to rectify this gap in knowledge, and explore new potential treatments based on targeting NMDA receptors with drugs that reduce excitation. The aims of this research project are: (i) To use biochemical, structural biology and physiological methods to classify NMDA receptor mutations as loss- or gain-of-function and to uncover how different mutations affect the basic functions of the NMDA receptor; (ii) To explore novel therapeutic routes by testing drugs that block NMDA receptor activity for their effectiveness in restoring normal function in defective NMDA receptors; iii) To create new models of epilepsy by introducing NMDA receptor mutations into the mouse genome. It is our hope that a detailed understanding of the mechanisms underlying NMDA receptor dysfunction, signalling pathways and pharmacology will enable insights into the roles of NMDA receptors in health and disease.