@article{0f3b2bdef83a4e9ba5b9539024d4ae44,
title = "Synaptic dysregulation and hyperexcitability induced by intracellular amyloid beta oligomers",
abstract = "Intracellular amyloid beta oligomer (iAβo) accumulation and neuronal hyperexcitability are two crucial events at early stages of Alzheimer's disease (AD). However, to date, no mechanism linking iAβo with an increase in neuronal excitability has been reported. Here, the effects of human AD brain-derived (h-iAβo) and synthetic (iAβo) peptides on synaptic currents and action potential firing were investigated in hippocampal neurons. Starting from 500 pM, iAβo rapidly increased the frequency of synaptic currents and higher concentrations potentiated the AMPA receptor-mediated current. Both effects were PKC-dependent. Parallel recordings of synaptic currents and nitric oxide (NO)-associated fluorescence showed that the increased frequency, related to pre-synaptic release, was dependent on a NO-mediated retrograde signaling. Moreover, increased synchronization in NO production was also observed in neurons neighboring those dialyzed with iAβo, indicating that iAβo can increase network excitability at a distance. Current-clamp recordings suggested that iAβo increased neuronal excitability via AMPA-driven synaptic activity without altering membrane intrinsic properties. These results strongly indicate that iAβo causes functional spreading of hyperexcitability through a synaptic-driven mechanism and offers an important neuropathological significance to intracellular species in the initial stages of AD, which include brain hyperexcitability and seizures.",
keywords = "AMPA-R, hyperexcitability, intracellular amyloid beta, nitric oxide, synaptic dysregulation",
author = "Fernandez-Perez, {Eduardo J.} and Braulio Mu{\~n}oz and Bascu{\~n}an, {Denisse A.} and Christian Peters and Riffo-Lepe, {Nicolas O.} and Espinoza, {Maria P.} and Morgan, {Peter J.} and Caroline Filippi and Romain Bourboulou and Urmi Sengupta and Rakez Kayed and J{\'e}r{\^o}me Epsztein and Aguayo, {Luis G.}",
note = "Funding Information: The authors would like to thank Marco Fuenzalida, Juan Pablo Henriquez and Marcela Torrej{\'o}n for their invaluable comments and for helpful discussion. The authors also thank Agenor Limon and Lauren Aguayo for having read and provided useful suggestions to the manuscript. For technical support we thank: Laurie Aguayo, Carolina Benitez, C{\'e}sar Lara, Daniela Nova, Alejandra Ram{\'i}rez, Ixia Cid, Javiera Gavilan and Jocelin Gonz{\'a}lez. This work was supported by Fondecyt Grants 1140473 and 1180752 (LGA). EJFP was supported by PhD Conicyt fellowship 81150045. Funding Information: The authors would like to thank Marco Fuenzalida, Juan Pablo Henriquez and Marcela Torrej{\'o}n for their invaluable comments and for helpful discussion. The authors also thank Agenor Limon and Lauren Aguayo for having read and provided useful suggestions to the manuscript. For technical support we thank: Laurie Aguayo, Carolina Benitez, C{\'e}sar Lara, Daniela Nova, Alejandra Ram{\'i}rez, Ixia Cid, Javiera Gavilan and Jocelin Gonz{\'a}lez. This work was supported by Fondecyt Grants 1140473 and 1180752 (LGA). EJFP was supported by PhD Conicyt fellowship 81150045. Publisher Copyright: {\textcopyright} 2021 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.",
year = "2021",
month = sep,
doi = "10.1111/acel.13455",
language = "English (US)",
volume = "20",
journal = "Aging cell",
issn = "1474-9718",
publisher = "Wiley-Blackwell",
number = "9",
}