Synaptic dysregulation and hyperexcitability induced by intracellular amyloid beta oligomers

Eduardo J Fernandez‐perez (1) , Braulio Muñoz (1) , Denisse A Bascuñan (1) , Christian Peters (1) , Nicolas O Riffo‐lepe (1) , Maria P Espinoza (1) , Peter J Morgan (2) , Caroline Filippi (2) , Romain Bourboulou (2) , Urmi Sengupta (3, 4) , Rakez Kayed (5, 3) , Jérôme Epsztein (2) , Luis G Aguayo (1)

1 Universidad de Concepción - University of Concepcion [Chile]
2 INMED - INSERM U1249 - Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université]
3 George and Cynthia Mitchell Center for Neurodegenerative diseases
4 University of Texas Medical Branch at Galveston
5 UTMB - The University of Texas Medical Branch

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.

Mots clés: Alzheimer's disease; α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; amyloid precursor protein; APs; action potentials; Aβ; amyloidβ peptide; CLR; chelerythrine; eEPSC; evoked excitatory post-synaptic currents; eIPSC; 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; mEPSC; miniature excitatory post-synaptic currents; mIPSC; miniature inhibitory post-synaptic currents; mPSC; miniature post-synaptic currents; Na v; voltage-dependent sodium channel; nNOS; neuronal nitric oxide synthase; NO; nitric oxide; NOS; nitric

Domaines: Neurosciences [q-bio.NC]

Eduardo J Fernandez‐perez, Braulio Muñoz, Denisse A Bascuñan, Christian Peters, Nicolas O Riffo‐lepe, et al.. Synaptic dysregulation and hyperexcitability induced by intracellular amyloid beta oligomers. Aging Cell, 2021, ⟨10.1111/acel.13455⟩. ⟨hal-03328666⟩