Journal
JOURNAL OF NEUROCHEMISTRY
Volume 144, Issue 5, Pages 669-679Publisher
WILEY
DOI: 10.1111/jnc.14136
Keywords
Alzheimer's disease; cross-frequency coupling; GABA; hippocampus; prefrontal cortex; TgF344
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Funding
- Canadian Consortium on Neurodegeneration in Aging from the Canadian Institute of Health Research [CAN-137794]
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Alzheimer's disease (AD) is pathologically characterized by amyloid-beta peptide (A beta) accumulation, neurofibrillary tangle formation, and neurodegeneration. Preclinical studies on neuronal impairments associated with progressive amyloidosis have demonstrated some A-dependent neuronal dysfunction including modulation of gamma-aminobutyric acid-ergic signaling. The present work focuses on the early stage of disease progression and uses TgF344-AD rats that recapitulate a broad repertoire of AD-like pathologies to investigate the neuronal network functioning using simultaneous intracranial recordings from the hippocampus (HPC) and the medial prefrontal cortex (mPFC), followed by pathological analyses of gamma-aminobutyric acid (GABA(A)) receptor subunits alpha 1(,) alpha 5, and delta, and glutamic acid decarboxylases (GAD65 and GAD67). Concomitant to amyloid deposition and tau hyperphosphorylation, low-gamma band power was strongly attenuated in the HPC and mPFC of TgF344-AD rats in comparison to those in non-transgenic littermates. In addition, the phase-amplitude coupling of the neuronal networks in both areas was impaired, evidenced by decreased modulation of theta band phase on gamma band amplitude in TgF344-AD animals. Finally, the gamma coherence between HPC and mPFC was attenuated as well. These results demonstrate significant neuronal network dysfunction at an early stage of AD-like pathology. This network dysfunction precedes the onset of cognitive deficits and is likely driven by A beta and tau pathologies.
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