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mTORC1–S6K1 inhibition or mTORC2 activation improves hippocampal synaptic plasticity and learning in Angelman syndrome mice

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Abstract

Emerging evidence is implicating abnormal activation of the mechanistic target of rapamycin (mTOR) pathway in several monogenetic neuropsychiatric disorders, including Angelman syndrome (AS), which is caused by deficiency in maternally inherited UBE3A. Using an AS mouse model, we show that semi-chronic rapamycin treatment improves long-term potentiation (LTP) and actin polymerization in hippocampal slices, spine morphology, and fear-conditioning learning. Activity of mTORC1 and of its downstream substrate, S6K1, was increased in hippocampus of AS mice. However, mTORC2 activity, as reflected by PKCα levels, was decreased. Both increased mTORC1 and decreased mTORC2 activities were reversed by semi-chronic rapamycin treatment. Acute treatment of hippocampal slices from AS mice with rapamycin or an S6K1 inhibitor, PF4708671, improved LTP, restored actin polymerization, and normalized mTORC1 and mTORC2 activity. These treatments also reduced Arc levels in AS mice. Treatment with Torin 1, an inhibitor of both mTORC1 and mTORC2, partially rescued LTP and actin polymerization in hippocampal slices from AS mice, while partially impairing them in wild-type (WT) mice. Torin 1 decreased mTORC1 and increased mTORC2 activity in slices from AS mice but inhibited both mTORC1 and mTORC2 in WT mice. Finally, an mTORC2 activator, A-443654, increased hippocampal LTP in AS mice and actin polymerization in both WT and AS mice. Collectively, these results indicate that events set in motion by increased mTORC1 and decreased mTORC2 activities, including increased Arc translation and impaired actin remodeling, are crucial in AS pathogenesis. Therefore, selectively targeting these two master kinase complexes may provide new therapeutic approaches for AS treatment.

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Abbreviations

AMPAR:

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor

Arc:

Activity-regulated cytoskeleton-associated protein

AS:

Angelman syndrome

BDNF:

Brain-derived neurotrophic factor

CS:

Conditioned stimuli

F-actin:

Filamentous actin

i.p.:

Intraperitoneally

LTP:

Long-term potentiation

mTOR:

Mechanistic target of rapamycin

PBS:

Phosphate-buffered saline

PFA:

Paraformaldehyde

TBS:

Theta-burst stimulation

US:

Unconditioned stimuli

WT:

Wild-type

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Acknowledgments

This work was supported by Grants P01NS045260 (PI: Dr. C.M. Gall) and R01NS057128 from NINDS to MB and R15MH101703 from NIMH to XB. XB is also supported by funds from the Daljit and Elaine Sarkaria Chair.

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    Authors and Affiliations

    1. Department of Basic Medical Sciences, COMP, Western University of Health Sciences, 701 E. Second Street, Pomona, CA, 91766-1854, USA

      Jiandong Sun, Jennifer Tran, Patrick O’Neal & Xiaoning Bi

    2. Graduate College of Biomedical Sciences, Western University of Health Sciences, 701 E. Second Street, Pomona, CA, 91766, USA

      Yan Liu & Michel Baudry

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    1. Jiandong Sun
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    J. Sun and Y. Liu contributed equally to this work.

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    Sun, J., Liu, Y., Tran, J. et al. mTORC1–S6K1 inhibition or mTORC2 activation improves hippocampal synaptic plasticity and learning in Angelman syndrome mice. Cell. Mol. Life Sci. 73, 4303–4314 (2016). https://doi.org/10.1007/s00018-016-2269-z

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