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Altered intrinsic excitability of hippocampal CA1 pyramidal neurons in aged PDAPP mice

Amyloidopathy involves the accumulation of insoluble amyloid β (Aβ) species in the brain’s parenchyma and is a key histopathological hallmark of Alzheimer’s disease (AD). Work on transgenic mice that overexpress Aβ suggests that elevated Aβ levels in the brain are associated with aberrant epileptifo...

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Autores principales: Tamagnini, Francesco, Novelia, Janet, Kerrigan, Talitha L., Brown, Jon T., Tsaneva-Atanasova, Krasimira, Randall, Andrew D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4604241/
https://www.ncbi.nlm.nih.gov/pubmed/26528126
http://dx.doi.org/10.3389/fncel.2015.00372
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author Tamagnini, Francesco
Novelia, Janet
Kerrigan, Talitha L.
Brown, Jon T.
Tsaneva-Atanasova, Krasimira
Randall, Andrew D.
author_facet Tamagnini, Francesco
Novelia, Janet
Kerrigan, Talitha L.
Brown, Jon T.
Tsaneva-Atanasova, Krasimira
Randall, Andrew D.
author_sort Tamagnini, Francesco
collection PubMed
description Amyloidopathy involves the accumulation of insoluble amyloid β (Aβ) species in the brain’s parenchyma and is a key histopathological hallmark of Alzheimer’s disease (AD). Work on transgenic mice that overexpress Aβ suggests that elevated Aβ levels in the brain are associated with aberrant epileptiform activity and increased intrinsic excitability (IE) of CA1 hippocampal neurons. In this study we examined if similar changes could be observed in hippocampal CA1 pyramidal neurons from aged PDAPP mice (20–23 month old, Indiana mutation: V717F on APP gene) compared to their age-matched wild-type littermate controls. Whole-cell current clamp recordings revealed that sub-threshold intrinsic properties, such as input resistance, resting membrane potential and hyperpolarization activated “sag” were unaffected, but capacitance was significantly decreased in the transgenic animals. No differences between genotypes were observed in the overall number of action potentials (AP) elicited by 500 ms supra-threshold current stimuli. PDAPP neurons, however, exhibited higher instantaneous firing frequencies after accommodation in response to high intensity current injections. The AP waveform was narrower and shorter in amplitude in PDAPP mice: these changes, according to our in silico model of a CA1/3 pyramidal neuron, depended on the respective increase and reduction of K(+) and Na(+) voltage-gated channels maximal conductances. Finally, the after-hyperpolarization, seen after the first AP evoked by a +300 pA current injection and after 50 Hz AP bursts, was more pronounced in PDAPP mice. These data show that Aβ-overexpression in aged mice altered the capacitance, the neuronal firing and the AP waveform of CA1 pyramidal neurons. Some of these findings are consistent with previous work on younger PDAPP; they also show important differences that can be potentially ascribed to the interaction between amyloidopathy and ageing. Such a change of IE properties over time underlies that the increased incidence of seizure observed in AD patients might rely on different mechanistic pathways during progression of the disease.
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spelling pubmed-46042412015-11-02 Altered intrinsic excitability of hippocampal CA1 pyramidal neurons in aged PDAPP mice Tamagnini, Francesco Novelia, Janet Kerrigan, Talitha L. Brown, Jon T. Tsaneva-Atanasova, Krasimira Randall, Andrew D. Front Cell Neurosci Neuroscience Amyloidopathy involves the accumulation of insoluble amyloid β (Aβ) species in the brain’s parenchyma and is a key histopathological hallmark of Alzheimer’s disease (AD). Work on transgenic mice that overexpress Aβ suggests that elevated Aβ levels in the brain are associated with aberrant epileptiform activity and increased intrinsic excitability (IE) of CA1 hippocampal neurons. In this study we examined if similar changes could be observed in hippocampal CA1 pyramidal neurons from aged PDAPP mice (20–23 month old, Indiana mutation: V717F on APP gene) compared to their age-matched wild-type littermate controls. Whole-cell current clamp recordings revealed that sub-threshold intrinsic properties, such as input resistance, resting membrane potential and hyperpolarization activated “sag” were unaffected, but capacitance was significantly decreased in the transgenic animals. No differences between genotypes were observed in the overall number of action potentials (AP) elicited by 500 ms supra-threshold current stimuli. PDAPP neurons, however, exhibited higher instantaneous firing frequencies after accommodation in response to high intensity current injections. The AP waveform was narrower and shorter in amplitude in PDAPP mice: these changes, according to our in silico model of a CA1/3 pyramidal neuron, depended on the respective increase and reduction of K(+) and Na(+) voltage-gated channels maximal conductances. Finally, the after-hyperpolarization, seen after the first AP evoked by a +300 pA current injection and after 50 Hz AP bursts, was more pronounced in PDAPP mice. These data show that Aβ-overexpression in aged mice altered the capacitance, the neuronal firing and the AP waveform of CA1 pyramidal neurons. Some of these findings are consistent with previous work on younger PDAPP; they also show important differences that can be potentially ascribed to the interaction between amyloidopathy and ageing. Such a change of IE properties over time underlies that the increased incidence of seizure observed in AD patients might rely on different mechanistic pathways during progression of the disease. Frontiers Media S.A. 2015-10-14 /pmc/articles/PMC4604241/ /pubmed/26528126 http://dx.doi.org/10.3389/fncel.2015.00372 Text en Copyright © 2015 Tamagnini, Novelia, Kerrigan, Brown, Tsaneva-Atanasova and Randall. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution and reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Tamagnini, Francesco
Novelia, Janet
Kerrigan, Talitha L.
Brown, Jon T.
Tsaneva-Atanasova, Krasimira
Randall, Andrew D.
Altered intrinsic excitability of hippocampal CA1 pyramidal neurons in aged PDAPP mice
title Altered intrinsic excitability of hippocampal CA1 pyramidal neurons in aged PDAPP mice
title_full Altered intrinsic excitability of hippocampal CA1 pyramidal neurons in aged PDAPP mice
title_fullStr Altered intrinsic excitability of hippocampal CA1 pyramidal neurons in aged PDAPP mice
title_full_unstemmed Altered intrinsic excitability of hippocampal CA1 pyramidal neurons in aged PDAPP mice
title_short Altered intrinsic excitability of hippocampal CA1 pyramidal neurons in aged PDAPP mice
title_sort altered intrinsic excitability of hippocampal ca1 pyramidal neurons in aged pdapp mice
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4604241/
https://www.ncbi.nlm.nih.gov/pubmed/26528126
http://dx.doi.org/10.3389/fncel.2015.00372
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