Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA.
J Neurosci. 2010 Feb 24;30(8):3072-81. doi: 10.1523/JNEUROSCI.4603-09.2010.
At hippocampal excitatory synapses, endocannabinoids (eCBs) mediate two forms of retrograde synaptic inhibition that are induced by postsynaptic depolarization or activation of metabotropic glutamate receptors (mGluRs). The homer family of molecular scaffolds provides spatial organization to regulate postsynaptic signaling cascades, including those activated by mGluRs. Expression of the homer 1a (H1a) immediate-early gene produces a short homer protein that lacks the domain required for homer oligomerization, enabling it to uncouple homer assemblies. Here, we report that H1a differentially modulates two forms of eCB-mediated synaptic plasticity, depolarization-induced suppression of excitation (DSE) and metabotropic suppression of excitation (MSE). EPSCs were recorded from cultured hippocampal neurons and DSE evoked by a 15 s depolarization to 0 mV and MSE evoked by a type I mGluR agonist. Expression of H1a enhanced DSE and inhibited MSE at the same synapse. Many physiologically important stimuli initiate H1a expression including brain-derived neurotrophic factor (BDNF). Treating hippocampal cultures with BDNF increased transcription of H1a and uncoupled homer 1c-GFP (green fluorescent protein) clusters. BDNF treatment blocked MSE and enhanced DSE. Thus, physiological changes in H1a expression gate the induction pathway for eCB-mediated synaptic plasticity by uncoupling mGluR from eCB production.
在海马兴奋性突触后，内源性大麻素（eCBs）介导两种形式的逆行突触抑制作用，分别由突触后去极化或代谢型谷氨酸受体（mGluRs）激活诱导。 Homer 家族的分子支架提供空间组织来调节突触后信号级联反应，包括那些由 mGluRs 激活的级联反应。 Homer 1a（H1a）即时早期基因的表达产生一种短的 Homer 蛋白，它缺乏 Homer 寡聚化所需的结构域，使其能够分离 Homer 组装体。在这里，我们报告 H1a 差异调节两种形式的 eCB 介导的突触可塑性，去极化诱导的兴奋抑制（DSE）和代谢型抑制的兴奋（MSE）。培养的海马神经元记录 EPSCs，并通过 0 mV 的 15 秒去极化诱发 DSE，通过 I 型 mGluR 激动剂诱发 MSE。H1a 的表达增强了 DSE 并抑制了同一突触的 MSE。许多生理上重要的刺激引发 H1a 的表达，包括脑源性神经营养因子（BDNF）。用 BDNF 处理海马培养物增加了 H1a 的转录并分离了 Homer 1c-GFP（绿色荧光蛋白）簇。BDNF 处理阻断了 MSE 并增强了 DSE。因此，H1a 表达的生理变化通过分离 mGluR 与 eCB 产生来控制 eCB 介导的突触可塑性的诱导途径。
