Early-stage attenuation of phase-amplitude coupling in the hippocampus and medial prefrontal cortex in a transgenic rat model of Alzheimer's disease.

Alzheimer's disease (AD) is pathologically characterized by amyloid-β peptide (Aβ) accumulation, neurofibrillary tangle formation, and neurodegeneration. Preclinical studies on neuronal impairments associated with progressive amyloidosis have demonstrated some Aβ-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 (GABAA ) receptor subunits α1, α5, and δ, 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 Aβ and tau pathologies. This article is part of the Special Issue "Vascular Dementia".