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

Background 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 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. ### Competing Interest Statement The authors have declared no competing interest. * AMPA : α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid APs : Action potentials APP : Amyloid precursor protein Aβ : Amyloid-β peptide CLR : Chelerythrine EA : Alzheimer’s disease eEPSCs : Evoked excitatory post-synaptic currents elPSCs : Evoked inhibitory post-synaptic currents eNOS : Endothelial nitric oxide synthase h-iAβo : human AD brain-derived Aβ oligomers iAβo : synthetic intracellular Aβ oligomers iNOS : Inducible nitric oxide synthase mEPSCs : Miniature excitatory post-synaptic currents mIPSCs : Miniature inhibitory post-synaptic currents mPSCs : Miniature post-synaptic currents Nav : Voltage-dependent sodium channel nNOS : Neuronal nitric oxide synthase NO : Nitric oxide NOS : Nitric oxide synthase PKC : Protein kinase C PLC : Phospholipase C PSEN1 : Presenilin-1 TTX : Tetrodotoxin Vm : Membrane potential