Synaptic dysregulation and hyperexcitability induced by intracellular amyloid beta oligomers

Intracellular amyloid beta oligomer (iA beta o) accumulation and neuronal hyperexcitability are two crucial events at early stages of Alzheimer's disease (AD). However, to date, no mechanism linking iA beta o with an increase in neuronal excitability has been reported. Here, the effects of human AD brain-derived (h-iA beta o) and synthetic (iA beta o) peptides on synaptic currents and action potential firing were investigated in hippocampal neurons. Starting from 500 pM, iA beta o 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 iA beta o, indicating that iA beta o can increase network excitability at a distance. Current-clamp recordings suggested that iA beta o increased neuronal excitability via AMPA-driven synaptic activity without altering membrane intrinsic properties. These results strongly indicate that iA beta o 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.