Role of CaMKI in structural plasticity and memory

CaMKI 在结构可塑性和记忆中的作用

• 批准号: 312434-2010
• 负责人: Frankland, Paul
• 金额: $ 5.17万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2013
• 资助国家: 加拿大
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=526510
• 关键词: Role; CaMKI; structural; plasticity; memory

Long-term memory is thought to involve changes in the connections (synapses) between neurons. These changes may involve either the rapid modification of existing connections between neurons (e.g., synaptic plasticity) or slower structural changes leading to the addition/elimination of synapses and modulation of axonal and dendritic growth (structural plasticity). While previous studies have focused on the role of axonal and dendritic growth in the formation of neural circuits in the developing brain, less attention has been paid to how these forms of structural plasticity contribute to memory formation in the adult brain. Recently, two isoforms of the calcium/calmodulin kinase I (CaMKI-gamma and CaMKI-alpha) have been shown to play complementary roles dendritogenesis and axonogenesis in a cell culture system. Here we propose to explore the role of CaMKI-gamma and CaMKI-alpha in memory formation in the adult brain. In preliminary studies we have examined mice with a global deletion of CaMKI-gamma, and found that CaMKI-gamma heterozygous (CaMKI-gamma+/-) mice were impaired in contextual fear conditioning and spatial learning, consistent with the finding that disrupting CaMKI-gamma function disrupts dendritogenesis in cell culture. This raises the possibility that this kinase plays a key role in structural plasticity required for hippocampal memory in the adult brain. However, as in these global knockout mice CaMKI-gamma was constitutively deleted from all cells, it is not possible to tease apart the effects of the deletion on developmental vs. adult plasticity. In order to address this issue, we propose to use a cre-loxP strategy to restrict deletion of CaMKI-gamma and CaMKI-alpha to a) forebrain excitatory circuits (by crossing floxed CaMKI-gamma or -alpha mice with CaMKII-creERT2 mice), and b) adult-generated neurons (by crossing floxed CaMKI-gamma or -alpha mice with nestin-creERT2 mice) in adult mice. By using these different lines of transgenic mice expressing cre-recombinase under different promoters we are able to delete CaMKI-gamma and CaMKI-alpha in a temporally and cell-type specific manner, and explore the contribution of this kinase to structural plasticity and memory in the adult brain.

长期记忆被认为涉及神经元之间连接（突触）的变化。这些变化可能涉及神经元之间现有连接的快速修改（例如，突触可塑性）或较慢的结构变化导致突触的增加/消除以及轴突和树突生长的调节（结构可塑性）。虽然以前的研究集中在轴突和树突生长在发育中的大脑神经回路形成中的作用，但很少关注这些形式的结构可塑性如何有助于成年大脑的记忆形成。最近，钙/钙调蛋白激酶I的两种亚型（CaMKI-γ和CaMKI-α）已被证明在细胞培养系统中起着树突发生和轴突发生的互补作用。在这里，我们建议探索CaMKI-γ和CaMKI-α在成人大脑记忆形成中的作用。在初步研究中，我们已经检查了具有CaMKI-γ的整体缺失的小鼠，并且发现CaMKI-γ杂合（CaMKI-γ +/-）小鼠在情境恐惧条件反射和空间学习中受损，这与破坏CaMKI-γ功能破坏细胞培养物中的树突状细胞生成的发现一致。这提出了这种激酶在成年大脑海马记忆所需的结构可塑性中起关键作用的可能性。然而，由于在这些整体敲除小鼠中，CaMKI-γ从所有细胞中组成性缺失，因此不可能将缺失对发育与成人可塑性的影响分开。为了解决这个问题，我们提出使用cre-loxP策略来将CaMKI-γ和CaMKI-α的缺失限制于a）前脑兴奋性回路（通过将floxed CaMKI-γ或-α小鼠与CaMKII-creERT 2小鼠杂交）和B）成年小鼠中的成年产生的神经元（通过将floxed CaMKI-γ或-α小鼠与nestin-creERT 2小鼠杂交）。通过使用在不同启动子下表达cre重组酶的这些不同系的转基因小鼠，我们能够以时间和细胞类型特异性的方式删除CaMKI-γ和CaMKI-α，并探索这种激酶对成年大脑结构可塑性和记忆的贡献。