Working memory deficits and related disinhibition of the cAMP/PKA/CREB are alleviated by prefrontal α4β2*-nAChRs stimulation in aged mice
Working memory deficits and related disinhibition of the cAMP/PKA/CREB are alleviated by prefrontal α4β2*-nAChRs stimulation in aged mice
复制标题
DOI：
10.1016/j.neurobiolaging.2012.10.006
复制
发表时间：
2013-06
影响因子：
4.2
通讯作者：
M. Vandesquille;Mathieu Baudonnat;L. Decorte;C. Louis;P. Lestage;D. Béracochéa
中科院分区：
文献类型：
--
作者：
M. Vandesquille;Mathieu Baudonnat;L. Decorte;C. Louis;P. Lestage;D. Béracochéa
本研究探讨了选择性α4β2* 烟碱受体激动剂S 38232和胆碱酯酶抑制剂多奈哌齐对老年小鼠工作记忆的增强作用，以及它们对cAMP反应元件结合蛋白（CREB）磷酸化（pCREB）的影响。我们首先表明，老年小鼠表现出WM赤字和增加pCREB的前边缘皮层（PL）相比，年轻的小鼠，而没有修改出现在CA 1。此外，我们发现全身给予S 38232可恢复老年小鼠的WM，并减轻PL CREB过度磷酸化。然而，多奈哌齐通过增加CA 1中的pCREB来减轻年龄相关的记忆缺陷，而PL中的pCREB则不受影响。最后，而利多卡因输注在PL的神经元抑制似乎有害的年轻小鼠，Rp-cAMPS（一种化合物，已知抑制CREB磷酸化）或S 38232的输注拯救老年动物WM。因此，通过靶向PL的α4β2*-烟碱受体，S 38232消除了PL CREB的过度磷酸化，并恢复了老年小鼠的WM，这为治疗策略开辟了新的药理学前景。
The present study investigates in aged mice the working memory (WM) enhancing potential of the selective α4β2* nicotinic receptor agonist S 38232 as compared with the cholinesterase inhibitor donepezil, and their effect on cAMP response element binding protein (CREB) phosphorylation (pCREB) as a marker of neuronal activity. We first showed that aged mice exhibit a WM deficit and an increase of pCREB in the prelimbic cortex (PL) as compared with young mice, whereas no modification appears in the CA1. Further, we showed that systemic administration of S 38232 restored WM in aged mice and alleviated PL CREB overphosphorylation. Donepezil alleviated age-related memory deficits, however, by increasing pCREB in the CA1, while pCREB in PL remained unaffected. Finally, whereas neuronal inhibition by lidocaine infusion in the PL appeared deleterious in young mice, the infusion of Rp-cAMPS (a compound known to inhibit CREB phosphorylation) or S 38232 rescued WM in aged animals. Thus, by targeting the α4β2*-nicotinic receptor of the PL, S 38232 alleviates PL CREB overphosphorylation and restores WM in aged mice, which opens new pharmacologic perspectives of therapeutic strategy.