Singh Vineeta, Carman Melissa, Roeper Jochen, Bonci Antonello
Department of Neurology, University of California, San Francisco, Ernest Gallo Clinic and Research Center, Emeryville, CA 94608, USA.
Eur J Neurosci. 2007 Sep;26(6):1489-99. doi: 10.1111/j.1460-9568.2007.05781.x.
Degeneration of dopamine neurons in the substantia nigra pars compacta (SNc) plays an important role in the pathophysiology of neurodegenerative diseases like Parkinsonism and vascular dementia. SNc dopamine neurons both in vitro and in vivo show sensitivity to hypoxic/ischemic conditions and undergo degeneration. In acute brain slices, these dopamine neurons undergo hyperpolarization during hypoxia and hypoglycemia, which results in silencing of the neurons. However, the role that SNc excitatory synapses play in this process is poorly understood. Here we examined the effect of oxygen/glucose deprivation (OGD) on glutamatergic synaptic transmission in the SNc in a rat midbrain slice preparation. OGD for 5 min caused pre-synaptic ischemic long-term depression (iLTD) of glutamate transmission, as both alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid- and N-methyl-D-aspartate receptor-mediated synaptic currents in SNc dopamine neurons were depressed to a similar extent. This depression began immediately after exposure to OGD and was not recovered upon washout of OGD. Pharmacological studies revealed that the iLTD was triggered by a rise in post-synaptic intracellular calcium and mediated by activation of pre-synaptic adenosine A(1) receptors, which reduced glutamate-dependent synaptic transmission by activating ATP-dependent potassium channels. Furthermore, we observed that iLTD did not occlude tetanic long-term depression (LTD) at the SNc excitatory synapses, suggesting that these two forms of LTD involve different pathways. Taken together, our results showed that brief exposure to hypoxia and hypoglycemia results in LTD of synaptic activity at glutamatergic synapses onto SNc neurons and this phenomenon could represent a protective mechanism by reducing ischemia-induced excitotoxic injury to dopamine neurons.
黑质致密部（SNc）中多巴胺能神经元的退化在帕金森病和血管性痴呆等神经退行性疾病的病理生理学中起着重要作用。体外和体内的SNc多巴胺能神经元均对缺氧/缺血条件敏感并会发生退化。在急性脑片中，这些多巴胺能神经元在缺氧和低血糖期间会发生超极化，从而导致神经元沉默。然而，SNc兴奋性突触在这一过程中所起的作用却鲜为人知。在此，我们在大鼠中脑脑片制备中研究了氧/葡萄糖剥夺（OGD）对SNc中谷氨酸能突触传递的影响。5分钟的OGD导致谷氨酸传递的突触前缺血性长时程抑制（iLTD），因为SNc多巴胺能神经元中α-氨基-3-羟基-5-甲基异恶唑-4-丙酸和N-甲基-D-天冬氨酸受体介导的突触电流均受到相似程度的抑制。这种抑制在暴露于OGD后立即开始，并且在OGD洗脱后未恢复。药理学研究表明，iLTD是由突触后细胞内钙升高触发的，并由突触前腺苷A(1)受体的激活介导，该受体通过激活ATP依赖性钾通道来减少谷氨酸依赖性突触传递。此外，我们观察到iLTD不会阻断SNc兴奋性突触处的强直长时程抑制（LTD），这表明这两种形式的LTD涉及不同的途径。综上所述，我们的结果表明，短暂暴露于缺氧和低血糖会导致SNc神经元上谷氨酸能突触的突触活动出现LTD，并且这种现象可能代表一种保护机制，通过减少缺血诱导的多巴胺能神经元兴奋性毒性损伤来实现。
