BDNF-endocannabinoid interactions at neocortical inhibitory synapses require phospholipase C signaling.
BDNF-endocannabinoid interactions at neocortical inhibitory synapses require phospholipase C signaling.
复制标题
DOI：
10.1152/jn.00554.2013
复制
发表时间：
2014-03
影响因子：
2.5
通讯作者：
Liangfang Zhao;E. Levine
中科院分区：
文献类型：
--
作者：
Liangfang Zhao;E. Levine
内源性大麻素（endocannabinoids）和神经营养素，特别是脑源性神经营养因子（BDNF），是有效的突触调节剂，在整个前脑中表达，在许多行为过程中发挥关键作用。尽管 BDNF 对兴奋性突触的作用已得到很好的表征，但 BDNF 对抑制性突触的作用机制尚不清楚。此前我们发现 BDNF 通过突触后原肌球蛋白相关激酶受体 B (trkB) 受体诱导的内源性大麻素释放来抑制新皮质 2/3 层突触前 GABA 的释放。为了检查这种效应背后的细胞内信号通路，我们使用药理学方法和全细胞膜片钳技术，研究了幼年瑞士 CD1 小鼠脑切片中体感皮层的 2/3 层锥体神经元。我们的结果表明，磷脂酶 Cγ (PLCγ) 参与了 CB1 受体介导的 BDNF 突触效应，因为 BDNF 效应在广谱 PLC 抑制剂 U-73122 和 edelfosine 的存在下被阻断，而无活性类似物 U-73343 并没有改变 BDNF 对抑制性突触的抑制作用。代谢型谷氨酸受体 (mGluR) 介导的 PLCβ 激活也可以触发内源性大麻素的释放，并且 BDNF 已被证明可以增强自发的谷氨酸释放。然而，mGluR 拮抗剂 E4CPG 并不能阻断 BDNF 的作用。此外，BDNF 的作用独立于 trkB 受体激活下游的其他信号传导途径，即丝裂原激活蛋白激酶和磷酸肌醇 3 激酶途径，以及蛋白激酶 C 信号传导。
Endogenous cannabinoids (endocannabinoids) and neurotrophins, particularly brain-derived neurotrophic factor (BDNF), are potent synaptic modulators that are expressed throughout the forebrain and play critical roles in many behavioral processes. Although the effects of BDNF at excitatory synapses have been well characterized, the mechanisms of action of BDNF at inhibitory synapses are not well understood. Previously we have found that BDNF suppresses presynaptic GABA release in layer 2/3 of the neocortex via postsynaptic tropomyosin-related kinase receptor B (trkB) receptor-induced release of endocannabinoids. To examine the intracellular signaling pathways that underlie this effect, we used pharmacological approaches and whole cell patch-clamp techniques in layer 2/3 pyramidal neurons of somatosensory cortex in brain slices from juvenile Swiss CD1 mice. Our results indicated that phospholipase Cγ (PLCγ) is involved in the CB1 receptor-mediated synaptic effect of BDNF, because the BDNF effect was blocked in the presence of the broad-spectrum PLC inhibitors U-73122 and edelfosine, whereas the inactive analog U-73343 did not alter the suppressive effect of BDNF at inhibitory synapses. Endocannabinoid release can also be triggered by metabotropic glutamate receptor (mGluR)-mediated activation of PLCβ, and BDNF has been shown to enhance spontaneous glutamate release. An mGluR antagonist, E4CPG, however, did not block the BDNF effect. In addition, the effect of BDNF was independent of other signaling pathways downstream of trkB receptor activation, namely, mitogen-activated protein kinase and phosphoinositide 3-kinase pathways, as well as protein kinase C signaling.