Learning-induced and stathmin-dependent changes in microtubule stability are critical for memory and disrupted in ageing

TY - JOUR

T1 - Learning-induced and stathmin-dependent changes in microtubule stability are critical for memory and disrupted in ageing

AU - Uchida, Shusaku

AU - Martel, Guillaume

AU - Pavlowsky, Alice

AU - Takizawa, Shuichi

AU - Hevi, Charles

AU - Watanabe, Yoshifumi

AU - Kandel, Eric R.

AU - Alarcon, Juan Marcos

AU - Shumyatsky, Gleb P.

N1 - Funding Information: We thank Andre Sobel for providing the Stathmin4A mutant construct and antibodies against phospho-stathmin, Dusan Bartsch for providing the htTA construct, Li-Mei Lin for help with ES work, and Monica Mendelson and Mantu Bhaumik for help with generation of mouse strains. We are grateful to Bonnie Firestein, Kim McKim, Chris Rongo, as well as members of the Shumyatsky’s lab for comments on the manuscript. S.U. was supported by the postdoctoral fellowship from the Japan Society for the Promotion of Science (JSPS). G.P.S. was supported by the National Science Foundation, National Institutes of Health (R01 MH080328) and Whitehall Foundation (2008-12-104). Research funded in part by the New Jersey Governor’s Council for Medical Research and Treatment of Autism, Special Child Health and Early Intervention Services, New Jersey Department of Health and Senior Services.

PY - 2014/7/10

Y1 - 2014/7/10

N2 - 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.

AB - 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.

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U2 - 10.1038/ncomms5389

DO - 10.1038/ncomms5389

M3 - Article

C2 - 25007915

SN - 2041-1723

VL - 5

JO - Nature communications

JF - Nature communications

M1 - 4389

ER -