University of Connecticut Health Center, Department of Neuroscience, MC-3401, 263 Farmington Ave., Farmington, CT 06030, USA.
J Neurophysiol. 2010 Oct;104(4):1923-32. doi: 10.1152/jn.00472.2010. Epub 2010 Aug 18.
The neurotrophin brain-derived neurotrophic factor (BDNF) is a potent regulator of inhibitory synaptic transmission, although the locus of this effect and the underlying mechanisms are controversial. We explored a potential interaction between BDNF and endogenous cannabinoid (endocannabinoid) signaling because activation of type 1 cannabinoid (CB1) receptors potently regulates γ-aminobutyric acid (GABA) release and both trkB tyrosine kinase receptors and CB1 receptors are highly expressed at synapses in neocortical layer 2/3. Here, we found that the effects of BDNF at inhibitory cortical synapses are mediated by the release of endocannabinoids acting retrogradely at presynaptic CB1 receptors. Specifically, acute application of BDNF rapidly reduced the amplitude of inhibitory postsynaptic currents (IPSCs) via postsynaptic trkB receptor activation because intracellular delivery of the tyrosine kinase inhibitor K252a completely blocked the BDNF effect. Although triggered by postsynaptic trkB activation, BDNF exposure decreased presynaptic release probability, as evidenced by increases in the paired-pulse ratio and coefficient of variation of evoked responses. In addition, BDNF decreased the frequency but not the amplitude of action potential-independent miniature IPSCs and BDNF did not alter the postsynaptic response to locally applied GABA. These results suggest that BDNF induces the release of a retrograde messenger from the postsynaptic cell that regulates presynaptic neurotransmitter release. Consistent with a role for endocannabinoids as the retrograde signal, the effect of BDNF on IPSCs was blocked by CB1 receptor antagonists and was occluded by a cannabinoid receptor agonist. Furthermore, inhibiting endocannabinoid synthesis or transport also disrupted the BDNF effect, implicating postsynaptic endocannabinoid release triggered by BDNF.
神经营养因子脑源性神经营养因子（BDNF）是抑制性突触传递的有效调节剂，尽管其作用部位和潜在机制存在争议。我们探索了 BDNF 与内源性大麻素（内源性大麻素）信号之间的潜在相互作用，因为激活 1 型大麻素（CB1）受体可强烈调节γ-氨基丁酸（GABA）释放，而 trkB 酪氨酸激酶受体和 CB1 受体在新皮层 2/3 层的突触中高度表达。在这里，我们发现 BDNF 对抑制性皮质突触的作用是通过内源性大麻素逆行作用于突触前 CB1 受体释放介导的。具体来说，BDNF 的急性应用通过突触后 trkB 受体激活迅速降低抑制性突触后电流（IPSCs）的幅度，因为细胞内递送酪氨酸激酶抑制剂 K252a 完全阻断了 BDNF 的作用。尽管 BDNF 暴露通过突触后 trkB 激活触发，但它降低了突触前释放的可能性，这表现在引发反应的成对脉冲比和变异性系数增加。此外，BDNF 降低了动作电位非依赖性微小 IPSC 的频率但不改变局部应用 GABA 后的突触后反应。这些结果表明，BDNF 诱导从突触后细胞释放一种逆行信使，调节突触前神经递质释放。与内源性大麻素作为逆行信号的作用一致，BDNF 对 IPSC 的影响被 CB1 受体拮抗剂阻断，并且被大麻素受体激动剂阻断。此外，抑制内源性大麻素的合成或转运也破坏了 BDNF 的作用，这表明 BDNF 触发了突触后内源性大麻素的释放。
