Tonic enhancement of endocannabinoid-mediated retrograde suppression of inhibition by cholinergic interneuron activity in the striatum
Tonic enhancement of endocannabinoid-mediated retrograde suppression of inhibition by cholinergic interneuron activity in the striatum
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DOI：
10.1523/jneurosci.4644-06.2007
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发表时间：
2007-01-17
影响因子：
5.3
通讯作者：
Kano, Masanobu
中科院分区：
文献类型：
--
作者：
Narushima, Madoka;Uchigashima, Motokazu;Kano, Masanobu
纹状体中的紧张性活性胆碱能中间神经元调节中棘（MS）神经元的纹状体输出活动，并显着影响基底神经节的整体功能。这种调节的细胞机制尚未完全了解。在这里，我们表明，环境乙酰胆碱（ACh）来自紧张性活性胆碱能中间神经元组成性上调去极化诱导释放的内源性大麻素从MS神经元。释放的内源性大麻素通过逆行作用于突触前CB 1大麻素受体，引起对MS神经元的抑制性突触输入的短暂抑制。这种效应是由M-1亚型的毒蕈碱乙酰胆碱受体介导的，因为M-1基因敲除小鼠中毒蕈碱激动剂释放内源性大麻素的作用和环境乙酰胆碱引起的去极化诱导的内源性大麻素释放的增强都是缺乏的，并且被突触后输注鸟苷-5 '-O-（2-硫代二磷酸）阻断。通过抑制I-h电流抑制胆碱能中间神经元的自发放电减少了去极化诱导的内源性大麻素释放。相反，通过抑制胆碱酯酶升高环境乙酰胆碱浓度显着增强内源性大麻素的释放。来自胆碱能中间神经元和MS神经元的配对记录显示，单个胆碱能神经元的活性可以影响邻近MS神经元中的内源性大麻素介导的信号传导。这些结果清楚地表明，纹状体内源性大麻素介导的调制胆碱能中间神经元活性的控制下。免疫荧光和免疫电镜观察表明，多巴胺D-1或D-2受体阳性的MS神经元胞体和树突内均有M-1受体的密集分布。因此，我们已经公开了一种新的机制，毒蕈碱系统调节纹状体输出，并可能有助于运动控制。
Tonically active cholinergic interneurons in the striatum modulate activities of striatal outputs from medium spiny (MS) neurons and significantly influence overall functions of the basal ganglia. Cellular mechanisms of this modulation are not fully understood. Here we show that ambient acetylcholine (ACh) derived from tonically active cholinergic interneurons constitutively upregulates depolarizationinduced release of endocannabinoids from MS neurons. The released endocannabinoids cause transient suppression of inhibitory synaptic inputs to MS neurons through acting retrogradely onto presynaptic CB1 cannabinoid receptors. The effects were mediated by postsynaptic M-1 subtype of muscarinic ACh receptors, because the action of a muscarinic agonist to release endocannabinoids and the enhancement of depolarization-induced endocannabinoid release by ambient ACh were both deficient in M-1 knock-out mice and were blocked by postsynaptic infusion of guanosine-5'-O-(2-thiodiphosphate). Suppression of spontaneous firings of cholinergic interneurons by inhibiting I-h current reduced the depolarization-induced release of endocannabinoids. Conversely, elevation of ambient ACh concentration by inhibiting choline esterase significantly enhanced the endocannabinoid release. Paired recording from a cholinergic interneuron and an MS neuron revealed that the activity of single cholinergic neuron could influence endocannabinoid-mediated signaling in neighboring MS neurons. These results clearly indicate that striatal endocannabinoid-mediated modulation is under the control of cholinergic interneuron activity. By immunofluorescent and immunoelectron microscopic examinations, we demonstrated that M-1 receptor was densely distributed in perikarya and dendrites of dopamine D-1 or D-2 receptor-positive MS neurons. Thus, we have disclosed a novel mechanism by which the muscarinic system regulates striatal output and may contribute to motor control.