Mechanism of cannabinoid effects on long-term potentiation and depression in hippocampal CA1 neurons
Mechanism of cannabinoid effects on long-term potentiation and depression in hippocampal CA1 neurons
复制标题
DOI：
10.1523/jneurosci.19-16-06795.1999
复制
发表时间：
1999-08-15
影响因子：
5.3
通讯作者：
Sullivan, JM
中科院分区：
文献类型：
--
作者：
Misner, DL;Sullivan, JM
大麻素是大麻的活性成分，已知会损害学习和记忆。大麻素受体在海马体中高度表达，海马体是一个被认为在某些形式的学习和记忆中发挥重要作用的大脑区域。为了研究大麻素受体介导的海马功能缺陷对大麻产生的学习和记忆障碍的可能影响，我们研究了大麻素受体激活对海马切片中两种学习和记忆模型的影响，即长时程增强（LTP）和长期抑制（LTD）。虽然在 Mg2+ 存在的情况下，CA1 场电位的 LTP 和 LTD 会被大麻素受体激活阻断，但在 Mg2+ 去除后，它们可以被诱导。同样，当突触后膜在 LTP 或 LTD 诱导方案期间去极化时，全细胞 EPSC 的 LTP 和 LTD 在大麻素受体激动剂存在下未受损。大麻素受体激活还减少 EPSC 并增强配对脉冲促进，同时对自发微型 EPSC 的振幅没有影响。最后，与大麻素受体激活一样，腺苷受体激活对 LTP 的抑制可以通过破伤风期间去除 Mg2+ 或突触后膜去极化来克服。我们的结果表明，大麻素受体激活并不直接抑制负责长期突触可塑性的分子机制，而是通过将突触前神经递质释放减少到低于使突触后膜去极化以缓解 NMDA 受体的 Mg2+ 阻断所需的水平来损害 LTP 和 LTD。
Cannabinoids, the active constituents of marijuana, are known to impair learning and memory. Receptors for cannabinoids are highly expressed in the hippocampus, a brain region that is believed to play an important role in certain forms of learning and memory. To investigate the possible contribution of cannabinoid receptor-mediated deficits in hippocampal function to the learning and memory impairments produced by marijuana, we studied the effects of cannabinoid receptor activation on two models of learning and memory, long-term potentiation (LTP) and long-term depression (LTD), in hippocampal slices. Although LTP and LTD of CA1 field potentials were blocked by cannabinoid receptor activation in the presence of Mg2+, they could be induced after Mg2+ was removed. Similarly, LTP and LTD of whole-cell EPSCs were unimpaired in the presence of cannabinoid receptor agonist when the postsynaptic membrane was depolarized during the LTP or LTD induction protocol. Cannabinoid receptor activation also reduced EPSCs and enhanced paired-pulse facilitation, while having no effect on the amplitude of spontaneous miniature EPSCs. Finally, as with cannabinoid receptor activation, inhibition of LTP by adenosine receptor activation could be overcome by removal of Mg2+ or depolarization of the postsynaptic membrane during tetanus. Our results indicate that cannabinoid receptor activation does not directly inhibit the molecular mechanisms responsible for long-term synaptic plasticity but instead impairs LTP and LTD by reducing presynaptic neurotransmitter release to a level below that required to depolarize the postsynaptic membrane to relieve Mg2+ blockade of NMDA receptors.