Loss of Cdc42 leads to defects in synaptic plasticity and remote memory recall.
Loss of Cdc42 leads to defects in synaptic plasticity and remote memory recall.
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DOI：
10.7554/elife.02839
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发表时间：
2014-07-08
期刊：
影响因子：
7.7
通讯作者：
Yasuda R
中科院分区：
文献类型：
--
作者：
Kim IH;Wang H;Soderling SH;Yasuda R
cdc 42是一种对肌动蛋白骨架重组和细胞形态发生有重要作用的信号蛋白。然而，Cdc 42在突触可塑性和学习记忆等行为中的功能作用还不清楚。在这里，我们报告说，出生后前脑缺失Cdc 42导致突触可塑性和远程记忆回忆的赤字使用条件敲除Cdc 42。我们发现，Cdc 42的缺失损害的Schaffer侧支突触和突触后结构可塑性的树突棘在海马CA 1区锥体神经元的LTP。此外，Cdc 42的丢失并不影响记忆的获得，而是显著损害了远程记忆回忆。这些结果表明，Cdc 42的出生后功能可能是至关重要的突触可塑性在海马神经元，这有助于远程记忆回忆的能力。http://dx.doi.org/10.7554/eLife.02839.001神经元在称为突触的连接处相互通信，突触通常形成于一个神经元的树突和另一个神经元的轴突末端之间。树突是从细胞体伸出的突起，接受来自其他细胞的输入;轴突是一种电缆状结构，使神经元能够接触其他细胞。在大脑中被称为海马体的兴奋性神经元中，树突本身被称为棘的结构所覆盖，因此大多数突触形成于轴突末端（属于突触前细胞）和树突棘（位于突触后细胞）之间。海马体是形成长期记忆所必需的。突触的强度可以随着时间的推移而增加或减少，这种特性被称为突触可塑性。突触强度的变化被认为是学习和记忆的基础，突触强度的长期变化涉及树突棘数量和大小的增加或减少。这样的变化是可能的，因为脊柱有一个内部骨架，可以在几分钟内组装和拆卸。这种“重塑”过程是由一种称为小GTP酶的酶家族调节的。其中一种被称为Cdc 42，已被证明可以促进细胞培养中棘的形成和维持，但其在突触可塑性，学习和记忆中的作用仍然未知。现在，Kim，Wang等人已经使用了从前脑兴奋性神经元中删除Cdc 42的转基因小鼠来检查这种酶在活体动物中的功能。这些“基因敲除”的小鼠表现出海马体中树突棘数量的少量但具有统计学意义的减少。他们还显示，脊柱体积的变化较小，海马体的长期突触可塑性受损。当小鼠进行长期记忆测试时，它们学会了将一组特定的视觉线索与即将发生的电击联系起来，敲除小鼠表现良好长达几天。然而，当45天后再次测试相同的任务时，敲除小鼠的表现不如正常小鼠。考虑到长期突触可塑性在学习和记忆中的假定作用，这是令人惊讶的，并表明Cdc 42是“远程记忆”所必需的，这种记忆形式持续了许多天。在另一个使用水迷宫的记忆测试中也得到了类似的结果，在水迷宫中，动物必须记住隐藏平台的位置。正常的老鼠能记住30多天的位置。相比之下，基因敲除小鼠只能记住几天的位置。除了首次证明Cdc 42在活体动物突触可塑性中的作用外，Kim，Wang等人的工作还为这种酶在记忆中的功能提供了新的见解。需要进一步的工作来确定Cdc 42如何与突触上的其他蛋白质相互作用。DOI：http://dx.doi.org/10.7554/eLife.02839.002网站
Cdc42 is a signaling protein important for reorganization of actin cytoskeleton and morphogenesis of cells. However, the functional role of Cdc42 in synaptic plasticity and in behaviors such as learning and memory are not well understood. Here we report that postnatal forebrain deletion of Cdc42 leads to deficits in synaptic plasticity and in remote memory recall using conditional knockout of Cdc42. We found that deletion of Cdc42 impaired LTP in the Schaffer collateral synapses and postsynaptic structural plasticity of dendritic spines in CA1 pyramidal neurons in the hippocampus. Additionally, loss of Cdc42 did not affect memory acquisition, but instead significantly impaired remote memory recall. Together these results indicate that the postnatal functions of Cdc42 may be crucial for the synaptic plasticity in hippocampal neurons, which contribute to the capacity for remote memory recall. DOI: http://dx.doi.org/10.7554/eLife.02839.001 Neurons communicate with one another at junctions called synapses, which are typically formed between the dendrite of one neuron and the axon terminus of another. The dendrites are protrusions coming out of the cell body that receive inputs from other cells; the axon is a cable-like structure that enables neurons to contact other cells. In excitatory neurons in part of the brain called the hippocampus, the dendrites are themselves covered in structures called spines, so most synapses are formed between an axon terminus (belonging to the presynaptic cell) and a dendritic spine (on the postsynaptic cell). The hippocampus is necessary for the formation of long-term memories. The strength of a synapse can increase or decrease over time—a property that is called synaptic plasticity. Changes in the strength of synapses are thought to underlie learning and memory, and long-lasting changes in synaptic strength involve increases or decreases in the number and size of dendritic spines. Such changes are possible because spines have an internal skeleton that can be assembled and disassembled in a matter of minutes. This ‘remodeling’ process is regulated by a family of enzymes called small GTPases. One of these, known as Cdc42, has been shown to promote the formation and maintenance of spines in cell culture, but its role in synaptic plasticity, learning and memory remains unknown. Now, Kim, Wang et al. have used genetically modified mice who have had Cdc42 deleted from excitatory neurons in their forebrain to examine the functions of this enzyme in living animals. These ‘knockout’ mice showed a small but statistically significant reduction in the number of dendritic spines in the hippocampus. They also showed smaller changes in spine volume and impaired long-term synaptic plasticity in the hippocampus. When the mice performed long-term memory tests where they learnt to associate a specific set of visual cues with an impending electric shock, the knockout mice performed well for up to a few days. However, when tested again on the same task 45 days later, the knockout mice did not perform as well as normal mice. This is surprising, given the presumed role of long-term synaptic plasticity in learning and memory, and indicates that Cdc42 is required for ‘remote memory’, the form of memory lasting for many days. Similar results were obtained with another memory test using a water maze, where the animals have to remember the location of a hidden platform. Normal mice remember the location for more than 30 days. In contrast, the knockout mice could only remember the location for a few days. As well as providing the first demonstration of the role of Cdc42 in synaptic plasticity in live animals, the work of Kim, Wang et al. has provided new insights into the functions of this enzyme in memory. Further work is required to determine how Cdc42 interacts with other proteins present at synapses. DOI: http://dx.doi.org/10.7554/eLife.02839.002