報告題目：Regulation of synaptic and extrasynaptic NMDA glutamate receptor activity in midbrain dopaminergic neurons
報告人： Sue Jones, Ph.D
Department of Physiology, Development and Neuroscience
University of Cambridge
時 ? ?間： 2019年10月29日（星期二）上午11:10-11:50
地 ? ?點：生化樓三層中廳
Most excitatory synaptic transmission in the mammalian brain is mediated by glutamate postsynaptic ionotropic receptors. N-methyl-D-aspartate receptors (NMDARs) are Ca2+ permeable glutamate receptors that play important roles in neural development, synaptic plasticity and cell survival. When over-active during neuronal dysfunction, NMDARs are thought to contribute to excitotoxic cell death, and they are implicated in neurodegeneration (e.g. in Alzheimer’s and Parkinson’s disease), ischaemic stroke and epilepsy. Interestingly, NMDARs can autoregulate their own activity and surface density through a process known as ‘current rundown’. In substantia nigra pars compacta (SNc) dopaminergic (DA) neurons, we have observed NMDAR current rundown that was partly reduced by increasing intracellular Ca2+ buffering, by reducing Ca2+ influx, and by inhibiting the cysteine protease, calpain. Calpain may contribute to intracellular Ca2+ homeostasis in dopamine neurones by limiting Ca2+ influx through the NMDAR; this could be important for neuronal survival. In humans, SNc-DA neurons show profound pathology in Parkinson’s disease (PD), and high frequency bursts of glutamatergic stimulation of SNc are more commonly detected in PD patients. We therefore explored the effect of high frequency stimulation of excitatory synapses in SNc-DA neurons. We observed large and long lasting NMDAR-EPSCs; these were increased ?in amplitude and duration by a glutamate transporter blocker (TBOA), indicating that ‘spill over’ of glutamate beyond the synapse may be regulated by glutamate transporters, thus limiting activation of extrasynaptic NMDARs. We also observed an increase in tonic NMDAR current with TBOA, indicating that glutamate transporters minimize tonic activity of NMDARs due to ambient glutamate. Overall, defects in the mechanisms of regulation of NMDAR activity of SNc-DA neurons could have adverse consequences for neuronal survival, and may contribute to neurodegeneration.
Dr Sue Jones is a Principal Investigator at the University of Cambridge, where her lab studies the properties and regulation of NMDA glutamate receptors in dopamine neurons; these are the cells primarily affected in Parkinson’s disease. Sue obtained her PhD in Neuropharmacology at University College London, working with Professor David Brown on the modulation of voltage-dependent potassium ion channels. She then moved to the USA to carry out postdoctoral research with Dr Jerry Yakel at NIH, working on nicotinic acetylcholine and serotonin receptor ion channels, and with Dr Julie Kauer at Duke University and Brown University, studying the effects of drugs of abuse on glutamatergic synaptic plasticity in midbrain dopamine neurons. ?She moved to the University of Cambridge to start her own lab in 2002, where she is currently a Senior Lecturer in the Department of Physiology, Development & Neuroscience. Her lab studies glutamatergic synapses in the mammalian brain and has a general interest in normal synaptic function and dysfunction in brain disorders, with a particular focus on NMDA receptors in midbrain dopamine neurons. She also teaches undergraduate medical and science students in Neuroscience, Physiology and Anatomy, serves on the Departmental Management Committee and is the Chair of the PDN Communications Committee.