Sex-dependent alterations in social behaviour and cortical synaptic activity coincide at different ages in a model of Alzheimer's disease.
Sex-dependent alterations in social behaviour and cortical synaptic activity coincide at different ages in a model of Alzheimer's disease.
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DOI：
10.1371/journal.pone.0046111
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Calon F
中科院分区：
文献类型：
--
作者：
Bories C;Guitton MJ;Julien C;Tremblay C;Vandal M;Msaid M;De Koninck Y;Calon F
除了记忆缺陷之外，阿尔茨海默病（AD）患者还患有神经精神症状，包括社会互动的改变，这是越来越多的AD转基因模型研究的主题。然而，这些行为改变背后的生物学机制却知之甚少。在这里，社交互动范例被用来评估AD的三重转基因小鼠模型（3xTg-AD）中的社交功能障碍。我们观察到转基因小鼠在不同年龄表现出二态性行为异常。与年龄和性别匹配的对照小鼠相比，在18个月大的3xTg-AD雄性中观察到社交去抑制。在3xTg-AD女性中，12个月时出现社交抑制解除，18个月时社交互动减少。这些二态行为改变与AD神经病理学标志物（如额叶皮质中的Aβ或tau水平）的改变无关。然而，膜片钳记录显示，增强社会互动的时间一致的增加兴奋性和抑制性的基础突触输入层2-3锥体神经元在前额叶皮层。这些发现揭示了AD模型中两性之间精神病样症状发生的新模式。我们的研究结果还表明，突触活动的功能改变出现作为一个潜在的显着基板的行为相关的AD。
Besides memory deficits, Alzheimer’s disease (AD) patients suffer from neuropsychiatric symptoms, including alterations in social interactions, which are subject of a growing number of investigations in transgenic models of AD. Yet the biological mechanisms underlying these behavioural alterations are poorly understood. Here, a social interaction paradigm was used to assess social dysfunction in the triple-transgenic mouse model of AD (3xTg-AD). We observed that transgenic mice displayed dimorphic behavioural abnormalities at different ages. Social disinhibition was observed in 18 months old 3xTg-AD males compared to age and sex-matched control mice. In 3xTg-AD females, social disinhibition was present at 12 months followed by reduced social interactions at 18 months. These dimorphic behavioural alterations were not associated with alterations in AD neuropathological markers such as Aβ or tau levels in the frontal cortex. However, patch-clamp recordings revealed that enhanced social interactions coincided temporally with an increase in both excitatory and inhibitory basal synaptic inputs to layer 2–3 pyramidal neurons in the prefrontal cortex. These findings uncover a novel pattern of occurrence of psychiatric-like symptoms between sexes in an AD model. Our results also reveal that functional alterations in synapse activity appear as a potentially significant substrate underlying behavioural correlates of AD.
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