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Cited by 109Alzheimer's disease research and treatmentsNeuroscience and Neuropharmacology ResearchEpilepsy research and treatment

Early-onset network hyperexcitability in presymptomatic Alzheimer’s disease transgenic mice is suppressed by passive immunization with anti-human APP/Aβ antibody and by mGluR5 blockade

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Kazim, Syed F., Chuang, Shih-Chieh, Zhao, Wangfa, Wong, Robert K. S., Bianchi, Riccardo, Iqbal, Khalid·2017·Frontiers in Aging Neuroscience
DOI 10.3389/fnagi.2017.00071PMC PMC5364175
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Abstract

Cortical and hippocampal network hyperexcitability appears to be an early event in Alzheimer’s disease (AD) pathogenesis, and may contribute to memory impairment. It remains unclear if network hyperexcitability precedes memory impairment in mouse models of AD and what are the underlying cellular mechanisms. We thus evaluated seizure susceptibility and hippocampal network hyperexcitability at ~ 3 weeks of age [prior to amyloid β (Aβ) plaque deposition, neurofibrillary pathology, and cognitive impairment] in a triple transgenic mouse model of familial AD (3xTg-AD mouse) that harbors mutated human amyloid β precursor protein (APP), tau, and presenilin 1 (PS1) genes. Audiogenic seizures were elicited in a higher proportion of 3xTg-AD mice compared with wild type (WT) controls. Seizure susceptibility in 3xTg-AD mice was attenuated either by passive immunization with anti-human APP/Aβ antibody (6E10) or by blockade of metabotropic glutamate receptor 5 (mGluR5) with the selective antagonist, 2-methyl-6-(phenylethynyl)pyridine hydrochloride, MPEP. In in vitro hippocampal slices, suppression of synaptic inhibition with the GABAA receptor antagonist, bicuculline, induced prolonged epileptiform (>1.5 s in duration) ictal-like discharges in the CA3 neuronal network in the majority of the slices from 3xTg-AD mice. In contrast, only short epileptiform (<1.5 s in duration) interictal-like discharges were observed following bicuculline application in the CA3 region of WT slices. The ictal-like activity in CA3 region of the hippocampus was significantly reduced in the 6E10-immunized compared to the saline-treated 3xTg-AD mice. MPEP acutely suppressed the ictal-like discharges in 3xTg-AD slices. Remarkably, epileptiform discharge duration positively correlated with intraneuronal human (transgenic) APP/Aβ expression in the CA3 region of the hippocampus. Our data suggest that in a mouse model of familial AD, hypersynchronous network activity underlying seizure susceptibility precedes Aβ plaque pathology and memory impairment. This early-onset network hyperexcitability can be suppressed by passive immunization with an anti-human APP/Aβ antibody and by mGluR5 blockade in 3xTg-AD mice.

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  • Recent evidence indicates that the 3xTg-AD displays early changes in neuronal network and synaptic function, before the appearance of cognitive and physiological alterations.

    “Nevertheless, recent evidence indicates that the 3xTg-AD displays early changes in neuronal network and synaptic function, before the appearance of cognitive and physiological alterations (Chakroborty et al., 2012; Gatta et al., 2014; Kazim et al., 2017).”

    From Early stage alterations in white matter and decreased functional interhemispheric hippocampal connectivity in the 3xTg mouse model of Alzheimer’s disease. (2019) · cites this paper as Kazim et al., 2017

    The Discussion reports heightened CA3 network excitability in 3-week-old 3xTg-AD mice before amyloid plaques, neurofibrillary pathology, and memory impairment. It does not establish that synaptic function changed before physiological alterations generally; network hyperexcitability is itself a physiological change. (LLM, conf=0.84)

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Cited by

Sorted by citations

Authors
Kazim, S. F., Chuang, S.-C., Zhao, W., Wong, R. K. S., Bianchi, R., & Iqbal, K.
Affiliations
  • State University of New York (US)
  • SUNY Downstate Health Sciences University (US)
Corresponding author
  • Bianchi, Riccardo
  • Iqbal, Khalid
ORCID
Venue
Frontiers in Aging Neuroscience
Publisher
Frontiers Media SA
Published
2017-03-24
Volume
9
Pages
71-71
ISSN
1663-4365 (ISSN-L)
DOI
10.3389/fnagi.2017.00071
PMC
PMC5364175
OpenAlex
W2601085743
Cited by
109
References
18
Citations by year
2026: 10 · 2025: 13 · 2024: 10 · 2023: 17 · 2022: 15 · 2021: 12 · 2020: 13 · 2019: 11 · 2018: 7 · 2017: 1
FWCI
6.48
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Frontiers in Aging Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
SUNY Downstate Medical Center
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
Keywords
Alzheimer's disease, network hyperexcitability, preclinical Alzheimer's disease, 3xTg-AD mice, audiogenic seizures, seizure susceptibility, passive immunization, amyloid-beta, metabotropic glutamate receptor 5, MPEP, hippocampal CA3, epileptiform discharges, synaptic inhibition, GABAA receptor, familial Alzheimer's disease, memory impairment

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