Presynaptic cannabinoid sensitivity is a major determinant of depolarization-induced retrograde suppression at hippocampal synapses
Presynaptic cannabinoid sensitivity is a major determinant of depolarization-induced retrograde suppression at hippocampal synapses
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DOI：
10.1523/jneurosci.22-10-03864.2002
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发表时间：
2002-05-15
影响因子：
5.3
通讯作者：
Kano, M
中科院分区：
文献类型：
--
作者：
Ohno-Shosaku, T;Tsubokawa, H;Kano, M
最近的研究表明，内源性大麻素(Endocannabinoid)是以钙离子依赖的方式从去极化的突触后神经元释放出来的，并逆行作用于突触前大麻素受体，抑制抑制性或兴奋性神经递质的释放。这种类型的调制在海马体和小脑中被发现，被称为去极化诱导的抑制(DSI)或兴奋(DSE)。在这项研究中，我们定量研究了突触后去极化和大麻素激动剂对大鼠海马片和培养的兴奋性和抑制性突触的影响。我们发现，DSE和DSI都可以被诱导，但DSE远不如DSI显著。诱发DSE所需的去极化时间长于DSI。DSE的震级远小于DSI。为了探索这些差异的原因，我们在海马区培养中测试了EPSCs和IPSCs对大麻素激动剂WIN55,212-2的敏感性。IPSCs分为两个不同的群体，一个对WIN55,212-2高度敏感(在2 nM时阻断50%)，另一个不敏感。相反，EPSCs是同质的，对WIN55,212-2的敏感性很低(在60 nm处有50%的阻断)。我们估计，5秒的去极化将局部内源性大麻素浓度提高到相当于几个纳米分子的WIN55,212-2的水平。利用CB1基因敲除小鼠，我们证实了DSI和DSE都是由大麻素CB1受体介导的。这些结果表明，突触前大麻素敏感性是决定DSI和DSE程度的主要因素。
Recent studies have clarified that endogenous cannabinoids (endocannabinoids) are released from depolarized postsynaptic neurons in a Ca2+-dependent manner and act retrogradely on presynaptic cannabinoid receptors to suppress inhibitory or excitatory neurotransmitter release. This type of modulation has been found in the hippocampus and cerebellum and was called depolarization-induced suppression of inhibition (DSI) or excitation (DSE). In this study, we quantitatively examined the effects of postsynaptic depolarization and a cannabinoid agonist on excitatory and inhibitory synapses in rat hippocampal slices and cultures. We found that both DSE and DSI can be induced, but DSE was much less prominent than DSI. For the induction of DSE, the necessary duration of depolarization was longer than for DSI. The magnitude of DSE was much smaller than that of DSI. To explore the reasons for these differences, we tested the sensitivity of EPSCs and IPSCs to a cannabinoid agonist, WIN55,212-2, in hippocampal cultures. IPSCs were dichotomized into two distinct populations, one with a high sensitivity to WIN55,212-2 (50% block at 2 nM) and the other with no sensitivity. In contrast, EPSCs were homogeneous and exhibited a low sensitivity to WIN55,212-2 (50% block at 60 nM). We estimated that the 5 sec depolarization elevated the local endocannabinoid concentration to a level equivalent to several nanomoles of WIN55,212-2. Using CB1 knock-out mice, we verified that both DSI and DSE were mediated by the cannabinoid CB1 receptor. These results indicate that presynaptic cannabinoid sensitivity is a major factor that determines the extent of DSI and DSE.