Department of Physiology, Program in Neuroscience, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
J Neurosci. 2010 Apr 21;30(16):5724-9. doi: 10.1523/JNEUROSCI.0795-10.2010.
Fragile X syndrome (FXS) results from deficiency of fragile X mental retardation protein (FMRP). FXS is the most common heritable form of mental retardation, and is associated with the occurrence of seizures. Factors responsible for initiating FXS-related hyperexcitability are poorly understood. Many protein-synthesis-dependent functions of group I metabotropic glutamate receptors (Gp1 mGluRs) are exaggerated in FXS. Gp1 mGluR activation can mobilize endocannabinoids (eCBs) in the hippocampus and thereby increase excitability, but whether FMRP affects eCBs is unknown. We studied Fmr1 knock-out (KO) mice lacking FMRP to test the hypothesis that eCB function is altered in FXS. Whole-cell evoked IPSCs (eIPSCs) and field potentials were recorded in the CA1 region of acute hippocampal slices. Three eCB-mediated responses were examined: depolarization-induced suppression of inhibition (DSI), mGluR-initiated eCB-dependent inhibitory short-term depression (eCB-iSTD), and eCB-dependent inhibitory long-term depression (eCB-iLTD). Low concentrations of a Gp1 mGluR agonist produced larger eCB-mediated responses in Fmr1 KO mice than in wild-type (WT) mice, without affecting DSI. Western blots revealed that levels of mGluR1, mGluR5, or cannabinoid receptor (CB1R) were unchanged in Fmr1 KO animals, suggesting that the coupling between mGluR activation and eCB mobilization was enhanced by FMRP deletion. The increased susceptibility of Fmr1 KO slices to eCB-iLTD was physiologically relevant, since long-term potentiation of EPSP-spike (E-S) coupling induced by the mGluR agonist was markedly larger in Fmr1 KO mice than in WT animals. Alterations in eCB signaling could contribute to the cognitive dysfunction associated with FXS.
脆性 X 综合征（FXS）是由于脆性 X 智力迟钝蛋白（FMRP）缺乏引起的。FXS 是最常见的遗传性智力障碍形式，与癫痫发作的发生有关。引起 FXS 相关过度兴奋的因素知之甚少。许多 I 型代谢型谷氨酸受体（Gp1 mGluRs）的蛋白合成依赖性功能在 FXS 中被夸大。Gp1 mGluR 的激活可以动员海马体内的内源性大麻素（eCBs），从而增加兴奋性，但 FMRP 是否影响 eCBs 尚不清楚。我们研究了缺乏 FMRP 的 Fmr1 敲除（KO）小鼠，以测试 eCB 功能在 FXS 中改变的假说。在急性海马切片的 CA1 区记录全细胞诱发 IPSC（eIPSC）和场电位。检查了三种 eCB 介导的反应：去极化诱导的抑制抑制（DSI）、mGluR 引发的 eCB 依赖性抑制短时间压抑（eCB-iSTD）和 eCB 依赖性抑制长时压抑（eCB-iLTD）。在 Fmr1 KO 小鼠中，低浓度的 Gp1 mGluR 激动剂产生比野生型（WT）小鼠更大的 eCB 介导反应，而不影响 DSI。Western blot 显示，Fmr1 KO 动物中 mGluR1、mGluR5 或大麻素受体（CB1R）的水平没有改变，这表明 FMRP 缺失增强了 mGluR 激活和 eCB 动员之间的偶联。Fmr1 KO 切片对 eCB-iLTD 的敏感性增加具有生理相关性，因为 mGluR 激动剂诱导的 EPSP-尖峰（E-S）偶联的长时程增强在 Fmr1 KO 小鼠中比 WT 动物明显更大。eCB 信号的改变可能导致与 FXS 相关的认知功能障碍。
