Uchida Shusaku, Martel Guillaume, Pavlowsky Alice, Takizawa Shuichi, Hevi Charles, Watanabe Yoshifumi, Kandel Eric R, Alarcon Juan Marcos, Shumyatsky Gleb P
1] Department of Genetics, Rutgers University, Room 322 Life Sciences Building,145 Bevier Road, Piscataway, New Jersey 08854, USA [2] Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan [3].
1] Department of Genetics, Rutgers University, Room 322 Life Sciences Building,145 Bevier Road, Piscataway, New Jersey 08854, USA [2].
Nat Commun. 2014 Jul 10;5:4389. doi: 10.1038/ncomms5389.
Changes in the stability of microtubules regulate many biological processes, but their role in memory remains unclear. Here we show that learning causes biphasic changes in the microtubule-associated network in the hippocampus. In the early phase, stathmin is dephosphorylated, enhancing its microtubule-destabilizing activity by promoting stathmin-tubulin binding, whereas in the late phase these processes are reversed leading to an increase in microtubule/KIF5-mediated localization of the GluA2 subunit of AMPA receptors at synaptic sites. A microtubule stabilizer paclitaxel decreases or increases memory when applied at the early or late phases, respectively. Stathmin mutations disrupt changes in microtubule stability, GluA2 localization, synaptic plasticity and memory. Aged wild-type mice show impairments in stathmin levels, changes in microtubule stability and GluA2 localization. Blocking GluA2 endocytosis rescues memory deficits in stathmin mutant and aged wild-type mice. These findings demonstrate a role for microtubules in memory in young adult and aged individuals.
微管稳定性的变化调节着许多生物过程，但其在记忆中的作用仍不清楚。在这里，我们表明学习会导致海马体中微管相关网络发生双相变化。在早期阶段，微管解聚蛋白去磷酸化，通过促进微管解聚蛋白与微管蛋白的结合增强其微管去稳定活性，而在后期这些过程会逆转，导致AMPA受体的GluA2亚基在突触部位的微管/KIF5介导的定位增加。微管稳定剂紫杉醇分别在早期或晚期应用时会降低或增强记忆。微管解聚蛋白突变会破坏微管稳定性、GluA2定位、突触可塑性和记忆的变化。老年野生型小鼠在微管解聚蛋白水平、微管稳定性变化和GluA2定位方面表现出损伤。阻断GluA2内吞作用可挽救微管解聚蛋白突变体和老年野生型小鼠的记忆缺陷。这些发现证明了微管在年轻成年个体和老年个体记忆中的作用。
