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The positive allosteric modulator at mGlu2 receptors, LY487379, reverses the effects of chronic stress-induced behavioral maladaptation and synaptic dysfunction in the adulthood.
SYNAPSE ( IF 2.3 ) Pub Date : 2019-05-23 , DOI: 10.1002/syn.22101
Dalila Mango 1 , Alessandra Caruso 2 , Amira Saidi 1 , Robert Nisticò 1, 3 , Sergio Scaccianoce 2
Affiliation  

Chronic stress induces maladaptive neural responses in several brain areas including hippocampus. It has been demonstrated that chronic stress exposure induced a downregulation of the putative presynaptic type 2 metabotropic glutamate (mGlu2) receptors, which would reduce the negative feedback role exerted by these receptors. The reduced availability of these receptors would enhance glutamate overflow in the hippocampus, supporting the hypothesis that hippocampal glutamatergic neurotransmission plays a key etiopathological determinant in stress-induced neuropsychiatric disorders. Since modulation of glutamatergic neurotransmission has been shown to represent an interesting pharmacological tool to treat psychiatric disorders, in the present study we have investigated the effects of the mGlu2 receptor positive allosteric modulator (PAM) LY487379. The rational bases of our study were: (a) chronic restraint stress (CRS) application in C57/BALB6 mouse induced a loss of resilience at the behavioral, biochemical, and electrophysiological level; (b) a superimposed familiar stressor (restraint) but not unfamiliar (i.e., forced swim stress) completely reversed the effects of CRS. Using the CRS model, in the present study we have investigated the effects of LY487379, an mGlu2 PAM, as well as a superimposed familiar stressor (acute restraint stress-ARS), on the immobility time at the tail suspension test and electrophysiological profile of glutamatergic transmission in the dentate gyrus (DG).

中文翻译:

mGlu2受体的正变构调节剂LY487379可逆转成年期慢性应激诱导的行为适应不良和突触功能障碍的影响。

慢性应激会在包括海马在内的多个大脑区域诱发适应不良的神经反应。业已证明,慢性应激暴露会导致潜在的突触前2型代谢型谷氨酸(mGlu2)受体下调,这将减少这些受体发挥的负反馈作用。这些受体的可用性降低将增强海马中的谷氨酸溢出,支持以下假设:海马谷氨酸能神经传递在应激性神经精神疾病中起着关键的病因学决定作用。由于已显示出调节谷氨酸能神经传递代表了一种治疗精神疾病的有趣药理工具,因此在本研究中,我们研究了mGlu2受体阳性变构调节剂(PAM)LY487379的作用。我们研究的合理基础是:(a)在C57 / BALB6小鼠中应用慢性束缚应激(CRS)会在行为,生化和电生理水平上导致弹性丧失;(b)重叠的熟悉的压力源(约束)但不陌生的(即强迫游泳压力)完全逆转了CRS的作用。使用CRS模型,在本研究中,我们研究了mGlu2 PAM LY487379和叠加的熟悉的应激源(急性束缚应激-ARS)对尾部悬吊测试的固定时间和谷氨酸能的电生理特性的影响在齿状回(DG)中传播。(b)重叠的熟悉的压力源(约束)但不陌生的(即强迫游泳压力)完全逆转了CRS的作用。使用CRS模型,在本研究中,我们研究了mGlu2 PAM LY487379和叠加的熟悉的应激源(急性束缚应激-ARS)对尾部悬吊测试的固定时间和谷氨酸能的电生理特性的影响在齿状回(DG)中传播。(b)叠加的熟悉的压力源(约束)但不熟悉的压力(即强迫游泳压力)完全逆转了CRS的作用。使用CRS模型,在本研究中,我们研究了mGlu2 PAM LY487379和叠加的熟悉的应激源(急性束缚应激-ARS)对尾部悬吊测试的固定时间和谷氨酸能的电生理特性的影响在齿状回(DG)中传播。
更新日期:2019-11-01
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