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‐ADrats that recapitulate a broad repertoire ofAD‐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 andGAD67). Concomitant to amyloid deposition and tau hyperphosphorylation, low‐gamma band power was strongly attenuated in theHPCandmPFCof TgF344‐ADrats 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‐ADanimals. Finally, the gamma coherence betweenHPCandmPFCwas attenuated as well. These results demonstrate significant neuronal network dysfunction at an early stage ofAD‐like pathology. This network dysfunction precedes the onset of cognitive deficits and is likely driven by Aβ and tau pathologies. image This article is part of the Special Issue “Vascular Dementia” .