Ahnaou A, Langlois X, Steckler T, Bartolome-Nebreda J M, Drinkenburg W H I M
Department of Neuroscience, Janssen Research and Development, Turnhoutseweg 30, 2340, Beerse, Belgium,
Psychopharmacology (Berl). 2015 Mar;232(6):1107-22. doi: 10.1007/s00213-014-3746-4. Epub 2014 Oct 18.
Evidence is emerging that positive and negative modulation of the metabotropic glutamate (mGluR5) receptors has the potential for treating cognitive deficits and neuroprotection associated with psychiatric and neurodegenerative diseases, respectively. Sleep and synchronisation of disparate neuronal networks are critically involved in neuronal plasticity, and disturbance in vigilance states and cortical network connectivity contribute significantly to cognitive deficits described in schizophrenia and Alzheimer's disease. Here, we examined the circadian changes of mGluR5 density and the functional response to modulation of mGluR5 signaling.
The current study carried out in Sprague-Dawley rats quantified the density of mGluR5 across the light-dark cycle with autoradiography. The central activity of mGluR5 negative allosteric modulators (2-methyl-6-(phenylethynyl)pyridine (MPEP) and [(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) and positive allosteric modulators (S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-methanone (ADX47273) and (7S)-3-tert-butyl-7-[3-(4-fluoro-phenyl)-1,2,4-oxadiazol-5-yl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine (LSN2814617) was examined on sleep-wake architecture. The functional effect of mGluR5 modulation on cortical networks communication was described in freely moving animals.
The density of mGluR5 in the striatal, cortical, hippocampal and thalamic structures was unchanged across the light-dark cycle. Allosteric blockade of mGluR5 consistently consolidated deep sleep, enhanced sleep efficiency and elicited prominent functional coherent network activity in slow theta and gamma oscillations. However, allosteric activation of mGluR5 increased waking, decreased deep sleep and reduced functional network connectivity following the activation of slow alpha oscillatory activity.
This functional study differentiates the pharmacology of allosteric blockade of mGluR5 from that of allosteric activation and suggests that mGluR5 blockade enhances sleep and facilitates oscillatory network connectivity, both processes being known to have relevance in cognition processes.
越来越多的证据表明，代谢型谷氨酸（mGluR5）受体的正向和负向调节分别具有治疗与精神疾病和神经退行性疾病相关的认知缺陷和神经保护作用的潜力。睡眠以及不同神经元网络的同步化在神经元可塑性中起着关键作用，警觉状态和皮质网络连接性的紊乱对精神分裂症和阿尔茨海默病中所描述的认知缺陷有显著影响。在此，我们研究了mGluR5密度的昼夜变化以及对mGluR5信号调节的功能反应。
本研究在Sprague-Dawley大鼠中进行，用放射自显影法定量了明暗周期中mGluR5的密度。研究了mGluR5负性变构调节剂（2-甲基-6-（苯乙炔基）吡啶（MPEP）和[（2-甲基-1,3-噻唑-4-基）乙炔基]吡啶（MTEP））和正性变构调节剂（S-（4-氟苯基）-{3-[3-（4-氟苯基）-[1,2,4]恶二唑-5-基]-哌啶-1-基}-甲酮（ADX47273）和（7S）-3-叔丁基-7-[3-（4-氟苯基）-1,2,4-恶二唑-5-基]-5,6,7,8-四氢[1,2,4]三唑并[4,3-a]吡啶（LSN2814617）对睡眠-觉醒结构的中枢活性。在自由活动的动物中描述了mGluR5调节对皮质网络通信的功能作用。
纹状体、皮质、海马和丘脑结构中mGluR5的密度在明暗周期中没有变化。mGluR5的变构阻断持续巩固了深度睡眠，提高了睡眠效率，并在慢θ和γ振荡中引发了显著的功能相干网络活动。然而，mGluR5的变构激活增加了觉醒，减少了深度睡眠，并在慢α振荡活动激活后降低了功能网络连接性。
这项功能研究区分了mGluR受体变构阻断与变构激活的药理学差异，并表明mGluR5阻断增强了睡眠并促进了振荡网络连接性，这两个过程在认知过程中均具有相关性。
