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

J Neurochem. 2018 Mar;144(5):669-679. doi: 10.1111/jnc.14136. Epub 2017 Oct 10.


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".

Keywords: GABA; Alzheimer's disease; TgF344; cross-frequency coupling; hippocampus; prefrontal cortex.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / pathology
  • Alzheimer Disease / physiopathology*
  • Animals
  • Brain Waves
  • Disease Models, Animal
  • Female
  • Glutamate Decarboxylase / metabolism
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Hippocampus / physiopathology*
  • Male
  • Neural Pathways / physiopathology
  • Neurons / physiology*
  • Plaque, Amyloid / metabolism
  • Prefrontal Cortex / pathology
  • Prefrontal Cortex / physiopathology*
  • Rats, Inbred F344
  • Rats, Transgenic
  • Receptors, GABA-A / metabolism


  • Receptors, GABA-A
  • Glutamate Decarboxylase
  • glutamate decarboxylase 1
  • glutamate decarboxylase 2