"Mechanisms of NMDA receptor-mediated neuroprotection and excitotoxicity"
NMDA receptors are a subtype of ionotropic glutamate receptor with an important role in the physiology and pathophysiology of central neurons. Inappropriate levels of Ca2+ influx through the NMDA receptor can contribute to neuronal loss in acute trauma such as ischemia and traumatic brain injury, as well as certain neurodegenerative disorders such as Huntington’s disease. However, normal physiological patterns of NMDA receptor activity can promote neuroprotection against both apoptotic, oxidative and excitotoxic insults. As a result, NMDA receptor blockade can promote neuronal death outright or render them vulnerable to secondary trauma. Thus, responses to NMDA receptor activity follow a classical hormetic dose-response curve: both too much and too little can be harmful. Our laboratory contributes to a growing knowledge of the molecular mechanisms underlying both the neuroprotective and neurodestructive effects of NMDA receptor activity, as well as the factors that determine whether an episode of NMDA receptor activity is harmful or beneficial. The coordinated transcriptional changes that underlie NMDAR-dependent neuroprotective effects will be discussed, both in terms of the molecular mechanisms by which they are initiated, as well as the basis for their effect. Furthermore, research will be described that uncovers the role of different NMDAR subunits in promoting pro-death and pro-survival signalling, and the mechanisms involved. The use of human stem cell-based approaches to probe these signalling pathways will also be touched on. Increased understanding in these areas of NMDAR signalling is leading to new potential therapeutic targets and strategies for excitotoxic disorders, as well as an appreciation of the harmful consequences of NMDA receptor blockade. References Martel et al (2012). Neuron 74(3):543-56. Puddifoot et al (2012) J. Neurosci 32:6995-7000. Hardingham & Bading (2010). Nat. Rev. Neurosci. 11, 682-696. Léveillé et al (2010). J. Neurosci 30. 263-265. Papadia et al (2008). Nat. Neurosci 11, 476-487.