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

• 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
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2012.02.046

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.