Lotfipour Shahrdad, Mojica Celina, Nakauchi Sakura, Lipovsek Marcela, Silverstein Sarah, Cushman Jesse, Tirtorahardjo James, Poulos Andrew, Elgoyhen Ana Belén, Sumikawa Katumi, Fanselow Michael S, Boulter Jim
Department of Psychiatry, University of California, Los Angeles, Los Angeles, California 90095, USA.
Department of Neurobiology and Behavior, University of California, Irvine, Irvine, California 92612, USA.
Learn Mem. 2017 May 15;24(6):231-244. doi: 10.1101/lm.045369.117. Print 2017 Jun.
The absence of α2* nicotinic acetylcholine receptors (nAChRs) in oriens lacunosum moleculare (OLM) GABAergic interneurons ablate the facilitation of nicotine-induced hippocampal CA1 long-term potentiation and impair memory. The current study delineated whether genetic mutations of α2* nAChRs ( and ) influence hippocampus-dependent learning and memory and CA1 synaptic plasticity. We substituted a serine for a leucine (L9'S) in the α2 subunit (encoded by the gene) to make a hypersensitive nAChR. Using a dorsal hippocampus-dependent task of preexposure-dependent contextual fear conditioning, adolescent hypersensitive male mice exhibited impaired learning and memory. The deficit was rescued by low-dose nicotine exposure. Electrophysiological studies demonstrated that hypersensitive α2 nAChRs potentiate acetylcholine-induced ion channel flux in oocytes and acute nicotine-induced facilitation of dorsal/intermediate CA1 hippocampal long-term potentiation in mice. Adolescent male mice null for the α2 nAChR subunit exhibited a baseline deficit in learning that was not reversed by an acute dose of nicotine. These effects were not influenced by locomotor, sensory or anxiety-related measures. Our results demonstrated that α2* nAChRs influenced hippocampus-dependent learning and memory, as well as nicotine-facilitated CA1 hippocampal synaptic plasticity.
海马分子层内嗅区（OLM）的γ-氨基丁酸（GABA）能中间神经元中缺乏α2烟碱型乙酰胆碱受体（nAChRs），会消除尼古丁诱导的海马CA1区长时程增强（LTP）的易化作用，并损害记忆。当前的研究确定了α2 nAChRs的基因突变（ 和 ）是否会影响海马依赖性学习和记忆以及CA1区突触可塑性。我们在α2亚基（由 基因编码）中将一个亮氨酸替换为丝氨酸（L9'S），以制造一种超敏nAChR。利用一种依赖背侧海马的预暴露依赖性情境恐惧条件反射任务，青春期超敏 雄性小鼠表现出学习和记忆受损。低剂量尼古丁暴露可挽救这种缺陷。电生理研究表明，超敏α2 nAChRs增强了卵母细胞中乙酰胆碱诱导的离子通道通量，以及急性尼古丁诱导的 小鼠背侧/中间CA1区海马LTP的易化作用。α2 nAChR亚基缺失的青春期雄性小鼠在学习方面表现出基线缺陷，急性剂量的尼古丁无法逆转这种缺陷。这些效应不受运动、感觉或焦虑相关指标的影响。我们的结果表明，α2* nAChRs影响海马依赖性学习和记忆，以及尼古丁促进的CA1区海马突触可塑性。
