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

By L. Verret, E. Mann, G. B. Hang, A. Barth, I. Cobos, Kaitlyn Ho, N. Devidze, E. Masliah, A. Kreitzer, István Módy and 2 more. Cell, 2012

1,160 citations recorded by the source corpus.

SUMMARY Alzheimer's disease (AD) results in cognitive decline and altered network activity, but the mechanisms are unknown. To identify such mechanisms, 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.

Subfields: Cellular and Molecular Neuroscience, Cognitive Neuroscience, Physiology

View Paper: https://www.semanticscholar.org/paper/075283abf8a02f76ded716b3e5a23529d04d950d

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Citations in the corpus

Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer’s disease model (2012, background): “hAPPmice from line J20 (hAPPJ20 mice) have pathologically elevated levels of human Aβ in the brain and show neuronal network dysfunction, including frequent abnormal spiking activity and more intermittent epileptic seizures (12, 15, 17).”
Multi-sensory gamma stimulation ameliorates Alzheimer’s-associated pathology and improves cognition. (2019, background): “For instance, gamma oscillations (30–90 Hz), associated with numerous higher-order cognitive functions (Fries, 2009), are disrupted in several AD mouse models (Verret et al., 2012; Gillespie et al., 2016; Iaccarino et al., 2016).”
APP mouse models for Alzheimer's disease preclinical studies (2017, neutral): “…result where differences between first and second-generation mouse models are evident involved the reported down-regulation of Na v 1.1, a sodium channel expressed in PV-positive interneurons in the APP-Tg mouse line J20 and its resultant effect on epilepsy and AD phenotypes (Verret et al , 2012).”
Gamma Entrainment Improves Synchronization Deficits in Dementia Patients (2021, methodology): “Then, we used the Equation set (5) 526”
Neural Mechanisms Underlying Brain Gamma Entrainment after Periodic Auditory Stimulation at Gamma Frequency (2024, background): “Inhibitory gamma-band activity is decreased, while excitatory neurons become more active in the disrupted network after AD, and this produces more A  which further exacerbates the network’s wellness [2, 5–11].”