Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Enhances Hippocampal Synaptic Plasticity and Improves Memory Performance in Huntington's Disease
Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Enhances Hippocampal Synaptic Plasticity and Improves Memory Performance in Huntington's Disease
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DOI：
10.1007/s12035-018-0972-5
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发表时间：
2018-11-01
影响因子：
5.1
通讯作者：
Xifro, X.
中科院分区：
文献类型：
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作者：
Cabezas-Llobet, N.;Vidal-Sancho, L.;Xifro, X.
海马突触可塑性缺陷导致亨廷顿病（HD）的认知障碍。腺苷酸环化酶激活多肽（PACAP）是一种神经肽，主要通过PAC 1受体发挥神经保护作用。然而，PACAP在认知中的作用知之甚少，并且在亨廷顿病（HD）的背景下没有数据存在。在这里，我们研究了PACAP受体刺激增强HD记忆发展的能力。首先，我们观察到所有三种PACAP受体表达的海马下降，即，PAC 1、VPAC 1和VPAC 2在两种不同的HD小鼠模型R6/1和HdhQ 7/Q111中从认知功能障碍开始。在海马死后的人类样本中，我们发现PAC 1的特异性减少，而VPAC 1和VPAC 2受体没有变化。为了确定PACAP受体的激活是否有助于改善记忆表现，我们在认知障碍发作时对R6/1小鼠每天鼻内施用PACAP 38，持续7天。我们发现，PACAP治疗挽救了R6/1小鼠中的PAC 1水平，促进了海马脑源性神经营养因子的表达，并减少了突变亨廷顿蛋白聚集体的形成。此外，通过新型物体识别测试和T-迷宫自发交替任务分析，PACAP给药可以抵消R6/1小鼠的记忆缺陷。重要的是，PACAP对认知能力的影响与R6/1小鼠海马中VGlut-1和PSD 95免疫标记的增加有关。综上所述，这些结果表明，PACAP，通过刺激PAC 1受体，可能有治疗潜力，以抵消认知功能障碍引起的HD。
Deficits in hippocampal synaptic plasticity result in cognitive impairment in Huntington's disease (HD). Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide that exerts neuroprotective actions, mainly through the PAC1 receptor. However, the role of PACAP in cognition is poorly understood, and no data exists in the context of Huntington's disease (HD). Here, we investigated the ability of PACAP receptor stimulation to enhance memory development in HD. First, we observed a hippocampal decline of all three PACAP receptor expressions, i.e., PAC1, VPAC1, and VPAC2, in two different HD mouse models, R6/1 and HdhQ7/Q111, from the onset of cognitive dysfunction. In hippocampal post-mortem human samples, we found a specific decrease of PAC1, without changes in VPAC1 and VPAC2 receptors. To determine whether activation of PACAP receptors could contribute to improve memory performance, we conducted daily intranasal administration of PACAP38 to R6/1 mice at the onset of cognitive impairment for seven days. We found that PACAP treatment rescued PAC1 level in R6/1 mice, promoted expression of the hippocampal brain-derived neurotrophic factor, and reduced the formation of mutant huntingtin aggregates. Furthermore, PACAP administration counteracted R6/1 mice memory deficits as analyzed by the novel object recognition test and the T-maze spontaneous alternation task. Importantly, the effect of PACAP on cognitive performance was associated with an increase of VGlut-1 and PSD95 immunolabeling in hippocampus of R6/1 mice. Taken together, these results suggest that PACAP, acting through stimulation of PAC1 receptor, may have a therapeutic potential to counteract cognitive deficits induced in HD.