title: Inhibitory interneuron deficit links altered network activity and cognitive dysfunction in Alzheimer model.
abstract: 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.
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA.
authors.forename: Laure
authors.initials: L
authors.lastname: Verret
authors.forename: Edward O
authors.initials: EO
authors.lastname: Mann
authors.forename: Giao B
authors.initials: GB
authors.lastname: Hang
authors.forename: Albert M I
authors.initials: AM
authors.lastname: Barth
authors.forename: Inma
authors.initials: I
authors.lastname: Cobos
authors.forename: Kaitlyn
authors.initials: K
authors.lastname: Ho
authors.forename: Nino
authors.initials: N
authors.lastname: Devidze
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.forename: Anatol C
authors.initials: AC
authors.lastname: Kreitzer
authors.forename: Istvan
authors.initials: I
authors.lastname: Mody
authors.forename: Lennart
authors.initials: L
authors.lastname: Mucke
authors.forename: Jorge J
authors.initials: JJ
authors.lastname: Palop
mesh_terms: D000544:Alzheimer Disease / Q000503:physiopathology*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007395:Interneurons / Q000378:metabolism; D007858:Learning; D008568:Memory; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D015222:Sodium Channels / Q000378:metabolism; D013569:Synapses
chemical_list: D016564:Amyloid beta-Protein Precursor; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568242:SCN1A protein, human; C568249:Scn1a protein, mouse; D015222:Sodium Channels