科学研究

报告预告

中脑多巴胺能神经元中突触和突触外NMDA谷氨酸受体活性的调控

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2019-10-24

Chinese Institute for Brain Research, Beijing

 Seminar

 

Seminar Type

B-type

Preferred Location

Third Floor Lecture Hall, Jianzan Building (Phase I)

Chinese Institute for Brain Research, Beijing

Time

10:00-10:30  Monday,October 28th, 2019

Speaker

Susan Jones, Ph.D.

Department of Physiology,

Development and Neuroscience,

University of Cambridge

 


Susan Jones,博士

剑桥大学

生理、发育与神经科学系

 


Host

Dr. Magdalena J Koziol


Topic

Regulation of synaptic and extrasynaptic NMDA glutamate receptor activity in midbrain dopaminergic neurons


中脑多巴胺能神经元中突触和突触外NMDA谷氨酸受体活性的调控


Abstract

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.


哺乳动物大脑中大多数兴奋性突触传递是由突触后离子型谷氨酸受体介导的。 N-甲基-D-天冬氨酸受体(NMDARs)是Ca2+通透的谷氨酸受体,其在神经发育,突触可塑性和细胞存活中起着重要作用。在神经元功能障碍时, NMDA受体的过度兴奋被认为可导致细胞死亡,进而可引发神经退行性疾病(例如阿尔茨海默氏病和帕金森氏病),缺血性中风和癫痫。有趣的是,NMDA受体可以通过称为“电流迫降”的过程自动调节其自身的活性和表面密度。在黑质致密区(SNc)多巴胺能(DA)神经元中,我们观察到NMDA受体介导的电流下降,这是由细胞内Ca2+缓冲作用的增加,Ca 2+流入的减少和抑制半胱氨酸蛋白酶活性——钙蛋白酶而引起的。钙蛋白酶可通过限制经过NMDA受体的Ca2 +流入来维持多巴胺神经元的细胞内Ca2 +稳态;这对神经元的存活非常重要。帕金森患者的SNc-DA神经元具有明显的病理学特性,并且在帕金森患者中通常能检测到SNc的谷氨酸能刺激的高频发放。因此,我们探讨了SNc-DA神经元中兴奋性突触中高频刺激的影响。我们观察到强且持久的NMDAR-EPSCs(NMDA受体介导的兴奋性突触后电流),并且谷氨酸转运阻断剂(TBOA)可以在幅度和持续时间上增加NMDAR-EPSCs,这表明突触外的谷氨酸的“溢出”可能受谷氨酸转运蛋白的调节,因此限制了突触外NMDA受体的激活。我们还观察到TBOA引发的强直NMDA受体介导的电流增加,这表明谷氨酸转运蛋白最小化了由周围谷氨酸引起的NMDA受体介导的强直活性。总之,SNc-DA神经元的NMDA受体的活性调节机制的缺陷可能对神经元存活产生不利影响,并且可能会导致神经退行性疾病。


Dr Sue Jones is a Senior Lecturer and 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.