1. Synaptic dysregulation and hyperexcitability induced by intracellular amyloid beta oligomers
- Author
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Christian Peters, Jérôme Epsztein, Luis G. Aguayo, Rakez Kayed, Denisse Bascuñán, Urmi Sengupta, Peter James Morgan, Nicolas O Riffo-Lepe, Caroline Filippi, Braulio Muñoz, María Paz Espinoza, Romain Bourboulou, Eduardo J Fernández-Pérez, Universidad de Concepción - University of Concepcion [Chile], Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université] (INMED - INSERM U1249), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), George and Cynthia Mitchell Center for Neurodegenerative diseases, University of Texas Medical Branch at Galveston, The University of Texas Medical Branch (UTMB), and pellegrino, Christophe
- Subjects
AMPA‐R ,Aging ,neuronal nitric oxide synthase ,amyloidβ peptide ,CLR ,synaptic dysregulation ,amyloid precursor protein ,Hippocampal formation ,chemistry.chemical_compound ,0302 clinical medicine ,human AD brain-derived Aβ oligomers ,Amyloid precursor protein ,miniature excitatory post-synaptic currents ,miniature post-synaptic currents ,chelerythrine ,evoked excitatory post-synaptic currents ,action potentials ,Aβ ,APs ,0303 health sciences ,hyperexcitability ,eEPSC ,mIPSC ,Alzheimer's disease ,eIPSC ,NOS ,Original Papers ,iNOS ,mEPSC ,eNOS ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Intracellular ,α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ,synthetic Intracellular Aβ oligomers ,Amyloid beta ,Na v ,nNOS ,AMPA receptor ,Biology ,intracellular amyloid beta ,Nitric oxide ,voltage-dependent sodium channel ,NO ,03 medical and health sciences ,nitric oxide ,nitric ,mPSC ,[SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,030304 developmental biology ,endothelial nitric oxide synthase ,Original Paper ,inducible nitric oxide synthase ,Cell Biology ,evoked inhibitory post-synaptic currents ,Chelerythrine ,chemistry ,miniature inhibitory post-synaptic currents ,biology.protein ,Retrograde signaling ,h-iAβo ,Neuroscience ,iAβo ,030217 neurology & neurosurgery - 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., In the presence of iAβo, PKC is activated (a), which in turn allows the production of nitric oxide (NO) at the post‐synaptic level, increasing the release of neurotransmitters (b) (evidenced as an increase in the frequency of mPSC). PKC also increases AMPA receptor current (c), increasing post‐synaptic depolarization and neuronal excitability (d). Finally, iAβo increases synchronization NO production in nearby neurons that do not have iAβo (e).
- Published
- 2021
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