Role of CaMKI in structural plasticity and memory

长期记忆被认为与神经元之间连接（突触）的变化有关。这些变化可能涉及神经元之间现有连接的快速改变（例如，突触可塑性）或导致突触增加/消除和轴突和树突生长调节的较慢的结构变化（结构可塑性）。虽然以前的研究主要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，但很少有人关注这些形式的结构可塑性如何在成人大脑中促进记忆的形成。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树突发生和轴突发生中起互补作用。在此，我们拟探讨camki - γ和camki - α在成人大脑记忆形成中的作用。在初步研究中，我们检测了camki - γ缺失的小鼠，发现camki - γ杂合（camki - γ +/-）小鼠在情境恐惧条件反射和空间学习方面受损，这与破坏camki - γ功能破坏细胞培养中树突发生的发现一致。这提出了这种激酶在成人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，由于在这些全球基因敲除小鼠中，camki - γ从所有细胞中组成性地缺失，因此不可能梳理出缺失对发育和成年可塑性的影响。为了解决这个问题，我们建议使用cre-loxP策略将CaMKI-gamma和CaMKI-alpha的缺失限制在a)成年小鼠的前脑兴奋回路（通过将CaMKI-gamma或-alpha小鼠与camki - creert2小鼠杂交）和b)成年生成的神经元（通过将CaMKI-gamma或-alpha小鼠与巢蛋白creert2小鼠杂交）。通过在不同启动子下表达cre-重组酶的不同转基因小鼠系，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，并探索该激酶对成人大脑结构可塑性和记忆的贡献。

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.