Neuron-specific caveolin-1 overexpression improves motor function and preserves memory in mice subjected to brain trauma
Neuron-specific caveolin-1 overexpression improves motor function and preserves memory in mice subjected to brain trauma
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DOI：
10.1096/fj.201601288rrr
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发表时间：
2017-08-01
期刊：
影响因子：
4.8
通讯作者：
Head, Brian P.
中科院分区：
文献类型：
--
作者：
Egawa, Junji;Schilling, Jan M.;Head, Brian P.
体外和体内研究表明，膜/脂筏和小窝蛋白（Cav）组织促生长受体，并且，当在神经元中特异性过表达时，Cav-1增强神经元信号传导和生长，并改善成年和老年小鼠的认知功能;然而，神经元Cav-1过表达是否可以在脑创伤环境中保留运动和认知功能尚不清楚。在这里，我们产生了一个神经元靶向的Cav-1过表达转基因（Tg）小鼠[突触蛋白驱动的Cav-1（SynCav 1 Tg）]，并将其进行脑创伤和测量的生化，解剖和行为变化的控制皮质影响模型。SynCav 1 Tg小鼠海马Cav-1表达增加，突触后密度蛋白95、NMDA受体和原肌球蛋白受体激酶B的膜/脂筏定位增加。当受到一个控制的皮质的影响，SynCav 1 Tg小鼠表现出保留海马依赖的恐惧学习和记忆，改善运动功能恢复，并减少脑损伤体积相比，野生型对照。Cav-1在成人大脑中的神经元靶向过表达可预防海马依赖性学习和记忆缺陷，恢复脑创伤后的运动功能，并减少创伤诱导的脑损伤大小。我们的研究结果表明，神经元靶向的Cav-1可以作为一种新的治疗策略，以恢复脑功能，防止创伤相关的适应不良的可塑性。
Studies in vitro and in vivo demonstrate that membrane/lipid rafts and caveolin (Cav) organize progrowth receptors, and, when overexpressed specifically in neurons, Cav-1 augments neuronal signaling and growth and improves cognitive function in adult and aged mice; however, whether neuronal Cav-1 overexpression can preserve motor and cognitive function in the brain trauma setting is unknown. Here, we generated a neuron-targeted Cav-1-overexpressing transgenic (Tg) mouse [synapsin-driven Cav-1 (SynCav1 Tg)] and subjected it to a controlled cortical impact model of brain trauma and measured biochemical, anatomic, and behavioral changes. SynCav1 Tg mice exhibited increased hippocampal expression of Cav-1 and membrane/lipid raft localization of postsynaptic density protein 95, NMDA receptor, and tropomyosin receptor kinase B. When subjected to a controlled cortical impact, SynCav1 Tg mice demonstrated preserved hippocampus-dependent fear learning and memory, improved motor function recovery, and decreased brain lesion volume compared with wild-type controls. Neuron-targeted overexpression of Cav-1 in the adult brain prevents hippocampus-dependent learning and memory deficits, restores motor function after brain trauma, and decreases brain lesion size induced by trauma. Our findings demonstrate that neuron-targeted Cav-1 can be used as a novel therapeutic strategy to restore brain function and prevent trauma associated maladaptive plasticity.