Synaptic dysregulation and hyperexcitability induced by intracellular amyloid beta oligomers.

Eduardo J Fernandez‐Perez,Denisse A Bascuñan,Rakez Kayed,Urmi Sengupta,Jérôme Epsztein,Nicolas O Riffo‐Lepe,Christian Peters,Peter J Morgan,Luis G Aguayo,Romain Bourboulou,Maria P Espinoza,Braulio Muñoz,Caroline Filippi

doi:10.1111/acel.13455

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.

Highlights

We examined the synaptic effects of human Alzheimer's disease (AD) brain-derived intracellular oligomers (h-intracellular accumulation of soluble Aβ oligomers (iAβo)) using an electrophysiological approach
Since our previous results showed an increase in iAβo-modulated neurotransmission and augmented spike number in current recording mode, we examined whether human AD brain-derived Aβ oligomers (h-iAβo) could affect glutamatergic vs GABAergic neurotransmission thereby changing the E/I balance in hippocampal neurons
We evaluated whether the effect of h-iAβo on the increase in action potentials (APs) firing could be the result of augmented transitory depolarizations at the post-synaptic level due to the increase in AMPAergic neurotransmission

Summary

| RESULTS

We examined the synaptic effects of human AD brain-derived intracellular oligomers (h-iAβo) using an electrophysiological approach. Since our previous results showed an increase in iAβo-modulated neurotransmission and augmented spike number in current recording mode, we examined whether h-iAβo could affect glutamatergic vs GABAergic neurotransmission thereby changing the E/I balance in hippocampal neurons. The data showed that there was a potent effect on the frequency of mPSC when iAβo was dialyzed into the post-synaptic neuron, suggesting an increase in the release of neurotransmitters at the pre- synaptic terminal (Malgaroli & Tsien, 1992). In order to examine this, we applied h-iAβo and recorded the membrane potential (Vm) fluctuations of cultured hippocampal neurons without current injection in the presence and the absence of an intracellular voltage-dependent sodium channel (Nav) blocker (5 mM QX-314). These data indicate that iAβo exerts depolarizations of the post- synaptic membrane even in the absence of APs, suggesting that this effect did not depend on the generation of APs at the post-synaptic level, but rather an increase in AMPA synaptic transmission at pre- and post-synaptic levels

| DISCUSSION

Findings

| EXPERIMENTAL PROCEDURES