Retrograde endocannabinoid signaling reduces GABAergic synaptic transmission to gonadotropin-releasing hormone neurons.
Retrograde endocannabinoid signaling reduces GABAergic synaptic transmission to gonadotropin-releasing hormone neurons.
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DOI：
10.1210/en.2010-0638
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发表时间：
2010-12
期刊：
影响因子：
4.8
通讯作者：
Liposits Z
中科院分区：
文献类型：
--
作者：
Farkas I;Kalló I;Deli L;Vida B;Hrabovszky E;Fekete C;Moenter SM;Watanabe M;Liposits Z
大麻素通过减少下丘脑GnRH输出来抑制生育能力。γ-氨基丁酸（GABA）A受体（GABAA-R）介导的传递是GnRH细胞的主要输入，可能是兴奋性的。我们假设大麻素通过抑制GABA能输入起作用。我们对成年雄性GnRH-绿色荧光蛋白转基因小鼠的急性脑片进行了散斑电生理研究。浴用1型大麻素受体（CB 1）激动剂WIN 55，212可降低GnRH神经元放电频率。这种作用在谷氨酸受体拮抗剂犬尿烯酸的存在下是可检测的，但当荷包牡丹碱也存在时消失，表明GABAA-R参与。在免疫细胞化学实验中，CB 1免疫反应性轴突与GnRH神经元形成接触，并且一个子集建立了GABA能神经传递特征的对称突触。在河豚毒素的存在下，用全细胞膜片钳电生理学继续进行功能研究。WIN 55，212降低了GABAA-R介导的微小突触后电流（mPSC）的频率（反映了自发的囊泡融合），这被CB 1拮抗剂AM 251阻止，共同表明突触前CB 1的激活抑制GABA的释放。AM 251单独增加mPSC频率，提供了内源性大麻素紧张性抑制GABAA-R驱动到GnRH神经元的证据。当用四氢利普他汀在细胞内阻断二酰甘油脂肪酶时，不存在mPSC频率增加，表明紧张性抑制是由GnRH神经元的2-花生四烯酸甘油产生引起的。细胞外液中的CdCl 2既能维持动作电位，又能维持自发囊泡融合。在这些条件下，当内源性大麻素介导的自发囊泡融合的阻断被AM 251阻断时，GnRH神经元放电增加，揭示了内源性大麻素对GnRH神经元放电的制动。在生理和病理条件下，逆行内源性大麻素信号传导可能是GnRH神经元调节其兴奋性GABA能输入的重要机制。GnRH神经元中合成的内源性大麻素通过抑制GABA能传入而降低GnRH神经元放电率。
Cannabinoids suppress fertility via reducing hypothalamic GnRH output. γ-Aminobutyric acid (GABA)A receptor (GABAA-R)-mediated transmission is a major input to GnRH cells that can be excitatory. We hypothesized that cannabinoids act via inhibiting GABAergic input. We performed loose-patch electrophysiological studies of acute slices from adult male GnRH-green fluorescent protein transgenic mice. Bath application of type 1 cannabinoid receptor (CB1) agonist WIN55,212 decreased GnRH neuron firing rate. This action was detectable in presence of the glutamate receptor antagonist kynurenic acid but disappeared when bicuculline was also present, indicating GABAA-R involvement. In immunocytochemical experiments, CB1-immunoreactive axons formed contacts with GnRH neurons and a subset established symmetric synapses characteristic of GABAergic neurotransmission. Functional studies were continued with whole-cell patch-clamp electrophysiology in presence of tetrodotoxin. WIN55,212 decreased the frequency of GABAA-R-mediated miniature postsynaptic currents (mPSCs) (reflecting spontaneous vesicle fusion), which was prevented with the CB1 antagonist AM251, indicating collectively that activation of presynaptic CB1 inhibits GABA release. AM251 alone increased mPSC frequency, providing evidence that endocannabinoids tonically inhibit GABAA-R drive onto GnRH neurons. Increased mPSC frequency was absent when diacylglycerol lipase was blocked intracellularly with tetrahydrolipstatin, showing that tonic inhibition is caused by 2-arachidonoylglycerol production of GnRH neurons. CdCl2 in extracellular solution can maintain both action potentials and spontaneous vesicle fusion. Under these conditions, when endocannabinoid-mediated blockade of spontaneous vesicle fusion was blocked with AM251, GnRH neuron firing increased, revealing an endogenous endocannabinoid brake on GnRH neuron firing. Retrograde endocannabinoid signaling may represent an important mechanism under physiological and pathological conditions whereby GnRH neurons regulate their excitatory GABAergic inputs. Endocannabinoids synthesized in GnRH neurons decrease GnRH neuron firing rate via inhibition of GABAergic afferents.
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影响因子：
5.3
作者：
Christian, Catherine A.;Moenter, Suzanne M.
通讯作者：
Moenter, Suzanne M.
DOI：
10.1073/pnas.0409641102
发表时间：
2005-06-28
影响因子：
11.1
作者：
Bernard, C;Milh, M;Gozlan, H
通讯作者：
Gozlan, H
影响因子：
5.5
作者：
Di, S;Boudaba, C;Tasker, JG
通讯作者：
Tasker, JG
影响因子：
3.6
作者：
DALTERIO, S;STEGER, R;DEPAOLO, L
通讯作者：
DEPAOLO, L
影响因子：
5.5
作者：
Huang, CC;Lo, SW;Hsu, KS
通讯作者：
Hsu, KS