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1. Kv1.1 contributes to a rapid homeostatic plasticity of intrinsic excitability in CA1 pyramidal neurons in vivo

Author

Peter James Morgan, Romain Bourboulou, Caroline Filippi, Julie Koenig-Gambini, and Jérôme Epsztein

Subjects
hippocampus, CA1 pyramidal cells, intrinsic excitability, long-term plasticity, memory, in vivo patch-clamp, Medicine, Science, Biology (General), QH301-705.5
Abstract

In area CA1 of the hippocampus, the selection of place cells to represent a new environment is biased towards neurons with higher excitability. However, different environments are represented by orthogonal cell ensembles, suggesting that regulatory mechanisms exist. Activity-dependent plasticity of intrinsic excitability, as observed in vitro, is an attractive candidate. Here, using whole-cell patch-clamp recordings of CA1 pyramidal neurons in anesthetized rats, we have examined how inducing theta-bursts of action potentials affects their intrinsic excitability over time. We observed a long-lasting, homeostatic depression of intrinsic excitability which commenced within minutes, and, in contrast to in vitro observations, was not mediated by dendritic Ih. Instead, it was attenuated by the Kv1.1 channel blocker dendrotoxin K, suggesting an axonal origin. Analysis of place cells’ out-of-field firing in mice navigating in virtual reality further revealed an experience-dependent reduction consistent with decreased excitability. We propose that this mechanism could reduce memory interference.

Published
2019
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2. Synaptic dysregulation and hyperexcitability induced by intracellular amyloid beta oligomers

Author

Christian Peters, Jérôme Epsztein, Luis G. Aguayo, Rakez Kayed, Denisse Bascuñán, Urmi Sengupta, Peter James Morgan, Nicolas O Riffo-Lepe, Caroline Filippi, Braulio Muñoz, María Paz Espinoza, Romain Bourboulou, Eduardo J Fernández-Pérez, Universidad de Concepción - University of Concepcion [Chile], Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université] (INMED - INSERM U1249), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), George and Cynthia Mitchell Center for Neurodegenerative diseases, University of Texas Medical Branch at Galveston, The University of Texas Medical Branch (UTMB), and pellegrino, Christophe

Subjects
AMPA‐R, Aging, neuronal nitric oxide synthase, amyloidβ peptide, CLR, synaptic dysregulation, amyloid precursor protein, Hippocampal formation, chemistry.chemical_compound, 0302 clinical medicine, human AD brain-derived Aβ oligomers, Amyloid precursor protein, miniature excitatory post-synaptic currents, miniature post-synaptic currents, chelerythrine, evoked excitatory post-synaptic currents, action potentials, Aβ, APs, 0303 health sciences, hyperexcitability, eEPSC, mIPSC, Alzheimer's disease, eIPSC, NOS, Original Papers, iNOS, mEPSC, eNOS, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Intracellular, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, synthetic Intracellular Aβ oligomers, Amyloid beta, Na v, nNOS, AMPA receptor, Biology, intracellular amyloid beta, Nitric oxide, voltage-dependent sodium channel, NO, 03 medical and health sciences, nitric oxide, nitric, mPSC, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], 030304 developmental biology, endothelial nitric oxide synthase, Original Paper, inducible nitric oxide synthase, Cell Biology, evoked inhibitory post-synaptic currents, Chelerythrine, chemistry, miniature inhibitory post-synaptic currents, biology.protein, Retrograde signaling, h-iAβo, Neuroscience, iAβo, 030217 neurology & neurosurgery
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., In the presence of iAβo, PKC is activated (a), which in turn allows the production of nitric oxide (NO) at the post‐synaptic level, increasing the release of neurotransmitters (b) (evidenced as an increase in the frequency of mPSC). PKC also increases AMPA receptor current (c), increasing post‐synaptic depolarization and neuronal excitability (d). Finally, iAβo increases synchronization NO production in nearby neurons that do not have iAβo (e).

Published
2021
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3. Functional spreading of hyperexcitability induced by human and synthetic intracellular Aβ oligomers

Author

Eduardo J Fernández-Pérez, Christian Peters, Urmi Sengupta, María Paz Espinoza, Luis G. Aguayo, Jerome Epsztein, Nicolas O Riffo-Lepe, Romain Bourboulou, Braulio Muñoz, Caroline Filippi, Rakez Kayed, Denisse Bascuñán, Peter James Morgan, Universidad de Concepción - University of Concepcion [Chile], Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université] (INMED - INSERM U1249), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), George and Cynthia Mitchell Center for Neurodegenerative diseases, The University of Texas Medical Branch (UTMB), University of Texas Medical Branch at Galveston, Universidad de Concepción [Chile], and Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)

Subjects
chemistry.chemical_compound, chemistry, nervous system, In vivo, Retrograde signaling, Biophysics, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], AMPA receptor, Hippocampal formation, Beta (finance), Ex vivo, Intracellular, Nitric oxide
Abstract

BackgroundIntracellular 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.MethodsHere, 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.ResultsStarting 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.ConclusionThese 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.

Published
2020

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