Dere E, Zlomuzica A, Viggiano D, Ruocco L A, Watanabe T, Sadile A G, Huston J P, De Souza-Silva M A
Institute of Physiological Psychology, Center for Biological and Medical Research, Heinrich-Heine-University of Düsseldorf, Universitätsstr. 1, D-40225 Düsseldorf, Germany.
Neuroscience. 2008 Dec 2;157(3):532-41. doi: 10.1016/j.neuroscience.2008.09.025. Epub 2008 Sep 25.
We investigated episodic-like (ELM) and procedural memory (PM) in histamine H1 receptor knockout (H1R-KO) mice. In order to relate possible behavioral deficits to neurobiological changes, we examined H1R-KO and wild-type (WT) mice in terms of acetylcholine esterase (AChE) activity in subregions of the hippocampus and AChE and tyrosine hydroxylase (TH) expression in the striatum. Furthermore, we analyzed acetylcholine (ACh), 5-HT and dopamine (DA) levels, including metabolites, in the cerebellum of H1R-KO and WT mice. The homozygous H1R-KO mice showed impaired ELM as compared with the heterozygous H1R-KO and WT mice. The performance of homozygous H1R-KO mice in the ELM task was primarily driven by familiarity-based memory processes. While the homozygous H1R-KO mice performed similar to the heterozygous H1R-KO and WT mice during the acquisition of a PM, as measured with an accelerating rotarod, after a retention interval of 7 days their performance was impaired relative to the heterozygous H1R-KO and WT mice. These findings suggest that, both, ELM and long-term PM are impaired in the homozygous H1R-KO mice. Neurochemical assays revealed that the H1R-KO mice had significantly lower levels of AChE activity in the dentate gyrus (DG) and CA1 subregions of the hippocampus as compared with the WT mice. The homozygous H1R-KO mice also displayed significantly reduced dihydroxyphenylacetic acid (DOPAC) levels and a reduced DOPAC/DA ratio in the cerebellum, suggesting that the DA turnover in the cerebellum is decelerated in homozygous H1R-KO mice. In conclusion, homozygous H1R-KO mice display severe long-term memory deficits in, both, ELM and PM, which coincide with changes in AChE activity in the hippocampus as well as DA turnover in the cerebellum. The importance of these findings for Alzheimer's (AD) and Parkinson's disease (PD) is discussed.
我们研究了组胺H1受体基因敲除（H1R-KO）小鼠的类情景记忆（ELM）和程序性记忆（PM）。为了将可能的行为缺陷与神经生物学变化联系起来，我们从海马体各亚区域的乙酰胆碱酯酶（AChE）活性以及纹状体中AChE和酪氨酸羟化酶（TH）的表达方面，对H1R-KO小鼠和野生型（WT）小鼠进行了检查。此外，我们分析了H1R-KO小鼠和WT小鼠小脑内乙酰胆碱（ACh）、5-羟色胺（5-HT）和多巴胺（DA）水平，包括其代谢产物。与杂合子H1R-KO小鼠和WT小鼠相比，纯合子H1R-KO小鼠表现出ELM受损。纯合子H1R-KO小鼠在ELM任务中的表现主要由基于熟悉度的记忆过程驱动。在用加速旋转棒测量时，虽然纯合子H1R-KO小鼠在获取PM期间的表现与杂合子H1R-KO小鼠和WT小鼠相似，但在7天的保留期后，它们的表现相对于杂合子H1R-KO小鼠和WT小鼠受损。这些发现表明，纯合子H1R-KO小鼠的ELM和长期PM均受损。神经化学分析显示，与WT小鼠相比，H1R-KO小鼠海马齿状回（DG）和CA1亚区域的AChE活性水平显著降低。纯合子H1R-KO小鼠在小脑中还表现出二羟基苯乙酸（DOPAC）水平显著降低以及DOPAC/DA比值降低，这表明纯合子H1R-KO小鼠小脑中的DA周转率减慢。总之，纯合子H1R-KO小鼠在ELM和PM方面均表现出严重的长期记忆缺陷，这与海马体中AChE活性的变化以及小脑中DA周转率的变化一致。本文讨论了这些发现对阿尔茨海默病（AD）和帕金森病（PD）的重要性。
