Functional spreading of hyperexcitability induced by human and synthetic intracellular Aβ oligomers [article]

Eduardo J Fernandez-Perez, Braulio Munoz, Denisse A Bascunan, Christian Peters, Nicolas O Riffo-Lepe, Maria P Espinoza, Peter J Morgan, Caroline Filippi, Romain Bourboulou, Urmi Sengupta, Rakez Kayed, Jerome Epsztein (+1 others)
2020 bioRxiv   pre-print
Intracellular amyloid-beta oligomers (iAβo) accumulation and neuronal hyperexcitability are two crucial events at early stages of Alzheimer's disease (AD). However, to date, no mechanism linking them has been reported. Methods: Here, the effects of human AD brain-derived (h-iAβo) and synthetic (iAβo) peptides on synaptic currents and action potential (AP) firing were investigated in hippocampal neurons in vitro, ex vivo and in vivo. Results: Starting from 500 pM, iAβo rapidly increased the
more » ... 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)-related fluorescence changes indicated 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. Conclusion: These results strongly indicate that iAβo causes functional spreading of hyperexcitability through a synaptic-driven mechanism and offer an important neuropathological significance to intracellular species in the initial stages of AD, which include brain hyperexcitability and seizures.
doi:10.1101/2020.10.16.332445 fatcat:m5nkjy6b65a57kewwbebhowdgq