Inhibitory Interneuron Deficit Links Altered Network Activity and Cognitive Dysfunction in Alzheimer Model

Alzheimer's disease (AD) results in cognitive decline and altered network activity, but the mechanisms are unknown. We studied human amyloid precursor protein (hAPP) transgenic mice, which simulate key aspects of AD. Electroencephalographic recordings in hAPP mice revealed spontaneous epileptif...

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Bibliographic Details
Published in:Cell 2012-04, Vol.149 (3), p.708-721
Main Authors: Verret, Laure, Mann, Edward O., Hang, Giao B., Barth, Albert M.I., Cobos, Inma, Ho, Kaitlyn, Devidze, Nino, Masliah, Eliezer, Kreitzer, Anatol C., Mody, Istvan, Mucke, Lennart, Palop, Jorge J.
Format: Article
Language:English
Subjects:
Alzheimer disease
Alzheimer Disease - physiopathology
Alzheimer's disease
amyloid
Amyloid beta-Protein Precursor - metabolism
Amyloid precursor protein
Animal models
Animals
cognition
Cognitive ability
Disease Models, Animal
EEG
electroencephalography
Firing pattern
Hippocampus - metabolism
Humans
In Vitro Techniques
Interneurons
Interneurons - metabolism
Learning
Life Sciences
Memory
Mice
Mice, Inbred C57BL
Mice, Transgenic
Mortality
NAV1.1 Voltage-Gated Sodium Channel
Nerve Tissue Proteins - metabolism
Neurodegenerative diseases
Neurons - metabolism
Neurons and Cognition
Oscillations
Parvalbumin
patients
Rhythms
sodium channels
Sodium channels (voltage-gated)
Sodium Channels - metabolism
Synapses
transgenic animals
Transgenic mice
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Summary:Alzheimer's disease (AD) results in cognitive decline and altered network activity, but the mechanisms are unknown. We studied human amyloid precursor protein (hAPP) transgenic mice, which simulate key aspects of AD. Electroencephalographic recordings in hAPP mice revealed spontaneous epileptiform discharges, indicating network hypersynchrony, primarily during reduced gamma oscillatory activity. Because this oscillatory rhythm is generated by inhibitory parvalbumin (PV) cells, network dysfunction in hAPP mice might arise from impaired PV cells. Supporting this hypothesis, hAPP mice and AD patients had decreased levels of the interneuron-specific and PV cell-predominant voltage-gated sodium channel subunit Nav1.1. Restoring Nav1.1 levels in hAPP mice by Nav1.1-BAC expression increased inhibitory synaptic activity and gamma oscillations and reduced hypersynchrony, memory deficits, and premature mortality. We conclude that reduced Nav1.1 levels and PV cell dysfunction critically contribute to abnormalities in oscillatory rhythms, network synchrony, and memory in hAPP mice and possibly in AD. [Display omitted] ▸ Network hypersynchrony emerges during reduced gamma oscillatory activity in hAPP mice ▸ PV cells in hAPP mice have reduced Nav1.1 levels and impaired functions ▸ Memory deficits in hAPP mice are linked to aberrant network hypersynchrony ▸ Restoring Nav1.1 levels improves network activity and memory functions in hAPP mice Depletion of a voltage-gated sodium channel in inhibitory interneurons is associated with abnormal patterns of neuronal activity and memory deficits in an hAPP mouse model of Alzheimer's disease (AD). Re-expression of this protein restores normal activity and oscillatory rhythms, ameliorating AD-associated memory deficits.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2012.02.046