Altered activity-rest patterns in mice with a human autosomal-dominant nocturnal frontal lobe epilepsy mutation in the β2 nicotinic receptor.
Altered activity-rest patterns in mice with a human autosomal-dominant nocturnal frontal lobe epilepsy mutation in the β2 nicotinic receptor.
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DOI：
10.1038/mp.2010.78
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发表时间：
2011-10
影响因子：
11
通讯作者：
Contractor, A.
中科院分区：
文献类型：
--
作者：
Xu, J.;Cohen, B. N.;Zhu, Y.;Dziewczapolski, G.;Panda, S.;Lester, H. A.;Heinemann, S. F.;Contractor, A.
含有β2亚基的高亲和力尼古丁受体(β2*)在大脑中广泛表达，调节许多神经元的过程，并参与阿尔茨海默病、帕金森病和癫痫等神经病理。α4和β2亚基的突变与一种罕见的部分性癫痫，常染色体显性遗传性夜间额叶癫痫有关。在这里，我们在小鼠基因组中引入了一个这样的人类错义突变，以产生一个携带Valine-to-Leucine突变的敲入菌株β2V287L。β2V287L小鼠是存活的，并以预期的孟德尔比率出生。令人惊讶的是，小鼠并没有表现出明显的癫痫表型；然而，纯合子小鼠的活动-休息模式确实显示出显著的变化。这表现为在光周期中活动增加，暗示小鼠的正常睡眠模式受到干扰；这种表型与人类ADNFLE患者的表型相似。与烟碱受体在奖赏通路中的作用一致，我们发现β2V287L小鼠没有发展出正常的自愿车轮跑步倾向，这是一种自然奖赏的模型。焦虑相关行为也受到V287L突变的影响。突变小鼠在高架加迷宫(EPM)上张开双臂的时间更长，这表明它们降低了焦虑水平。总之，这些发现强调了β2*尼古丁受体在复杂的生物过程中的几个重要作用，包括活动-休息周期、自然奖励和焦虑。
High-affinity nicotinic receptors containing beta2 subunits (β2*) are widely expressed in the brain, modulating many neuronal processes and contributing to neuropathologies such as Alzheimer’s disease, Parkinson’s disease and epilepsy. Mutations in both the α4 and β2 subunits are associated with a rare partial epilepsy, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Here we introduced one such human missense mutation into the mouse genome to generate a knock-in strain carrying a valine-to-leucine mutation β2V287L.β2V287L mice were viable and born at an expected Mendelian ratio. Surprisingly, mice did not display an overt seizure phenotype; however homozygous mice did display significant alterations in their activity-rest patterns. This was manifest as an increase in activity during the light cycle suggestive of disturbances in the normal sleep patterns of mice; a parallel phenotype to that found in human ADNFLE patients. Consistent with the role of nicotinic receptors in reward pathways, we found that β2V287L mice did not develop a normal proclivity to voluntary wheel running, a model for natural reward. Anxiety-related behaviors were also affected by the V287L mutation. Mutant mice spent more time in the open arms on the elevated plus maze (EPM) suggesting that they had reduced levels of anxiety. Together, these findings emphasize several important roles of β2* nicotinic receptors in complex biological processes including the activity-rest cycle, natural reward, and anxiety.
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影响因子：
1.6
作者：
Fowler CD;Arends MA;Kenny PJ
通讯作者：
Kenny PJ
影响因子：
3.6
作者：
Booker, T. K.;Butt, Christopher M.;Collins, Allan C.
通讯作者：
Collins, Allan C.
DOI：
10.1124/jpet.103.053066
发表时间：
2003-09-01
影响因子：
3.5
作者：
Dobelis, P;Hutton, S;Collins, AC
通讯作者：
Collins, AC
DOI：
10.1073/pnas.0807635105
发表时间：
2008-10-14
影响因子：
11.1
作者：
Avale, Maria Elena;Faure, Philippe;Maskos, Uwe
通讯作者：
Maskos, Uwe
影响因子：
3
作者：
Annegers, JF;Coan, SP
通讯作者：
Coan, SP