Ferrante Antonella, Boussadia Zaira, Borreca Antonella, Mallozzi Cinzia, Pedini Giorgia, Pacini Laura, Pezzola Antonella, Armida Monica, Vincenzi Fabrizio, Varani Katia, Bagni Claudia, Popoli Patrizia, Martire Alberto
National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Rome, Italy.
Institute of Neuroscience (IN)-CNR, Milan, Italy.
Transl Psychiatry. 2021 Feb 5;11(1):112. doi: 10.1038/s41398-021-01238-5.
In fragile X syndrome (FXS) the lack of the fragile X mental retardation protein (FMRP) leads to exacerbated signaling through the metabotropic glutamate receptors 5 (mGlu5Rs). The adenosine A receptors (ARs), modulators of neuronal damage, could play a role in FXS. A synaptic colocalization and a strong permissive interaction between A and mGlu5 receptors in the hippocampus have been previously reported, suggesting that blocking ARs might normalize the mGlu5R-mediated effects of FXS. To study the cross-talk between A and mGlu5 receptors in the absence of FMRP, we performed extracellular electrophysiology experiments in hippocampal slices of Fmr1 KO mouse. The depression of field excitatory postsynaptic potential (fEPSPs) slope induced by the mGlu5R agonist CHPG was completely blocked by the AR antagonist ZM241385 and strongly potentiated by the AR agonist CGS21680, suggesting that the functional synergistic coupling between the two receptors could be increased in FXS. To verify if chronic AR blockade could reverse the FXS phenotypes, we treated the Fmr1 KO mice with istradefylline, an AR antagonist. We found that hippocampal DHPG-induced long-term depression (LTD), which is abnormally increased in FXS mice, was restored to the WT level. Furthermore, istradefylline corrected aberrant dendritic spine density, specific behavioral alterations, and overactive mTOR, TrkB, and STEP signaling in Fmr1 KO mice. Finally, we identified AR mRNA as a target of FMRP. Our results show that the pharmacological blockade of ARs partially restores some of the phenotypes of Fmr1 KO mice, both by reducing mGlu5R functioning and by acting on other AR-related downstream targets.
在脆性X综合征（FXS）中，脆性X智力低下蛋白（FMRP）的缺乏导致通过代谢型谷氨酸受体5（mGlu5Rs）的信号传导加剧。腺苷A受体（ARs）作为神经元损伤的调节剂，可能在FXS中发挥作用。此前已有报道称，海马体中A受体与mGlu5受体存在突触共定位以及强烈的允许性相互作用，这表明阻断ARs可能使FXS中mGlu5R介导的效应恢复正常。为了研究在缺乏FMRP的情况下A受体与mGlu5受体之间的相互作用，我们在Fmr1基因敲除小鼠的海马切片上进行了细胞外电生理实验。mGlu5R激动剂CHPG诱导的场兴奋性突触后电位（fEPSPs）斜率降低被AR拮抗剂ZM241385完全阻断，并被AR激动剂CGS21680强烈增强，这表明在FXS中这两种受体之间的功能协同偶联可能增加。为了验证长期阻断ARs是否能逆转FXS表型，我们用AR拮抗剂异他林治疗Fmr1基因敲除小鼠。我们发现，在FXS小鼠中异常增加的海马二氢吡啶环丙烷谷氨酸（DHPG）诱导的长时程抑制（LTD）恢复到了野生型水平。此外，异他林纠正了Fmr1基因敲除小鼠中异常的树突棘密度、特定的行为改变以及过度活跃的mTOR、TrkB和STEP信号传导。最后，我们确定AR mRNA是FMRP的一个靶点。我们的结果表明，ARs的药理学阻断通过降低mGlu5R的功能以及作用于其他与AR相关的下游靶点，部分恢复了Fmr1基因敲除小鼠的一些表型。
