Electrophysiological Characterization of Networks and Single Cells in the Hippocampal Region of a Transgenic Rat Model of Alzheimer’s Disease

Abstract

The hippocampus and entorhinal cortex (EC) are areas affected early and severely in Alzheimer’s disease (AD), and this is associated with deficits in episodic memory. Amyloid-β (Aβ), the main protein found in amyloid plaques, can affect neuronal physiology and excitability, and several AD mouse models with memory impairments display aberrant network activity, including hyperexcitability and seizures. In this study, we investigated single cell physiology in EC and network activity in EC and dentate gyrus (DG) in the McGill-R-Thy1-APP transgenic rat model, using whole-cell patch clamp recordings and voltage-sensitive dye imaging (VSDI) in acute slices. In slices from transgenic animals up to 4 months of age, the majority of the principal neurons in Layer II of EC, fan cells and stellate cells, expressed intracellular Aβ (iAβ). Whereas the electrophysiological properties of fan cells were unaltered, stellate cells were more excitable in transgenic than in control rats. Stimulation in the DG resulted in comparable patterns in both groups at three and nine months, but at 12 months, the elicited responses in the transgenic group showed a significant preference for the enclosed blade, without any change in overall excitability. Only transient changes in the local network activity were seen in the medial EC (MEC). Although the observed changes in the McGill rat model are subtle, they are specific, pointing to a differential and selective involvement of specific parts of the hippocampal circuitry in Aβ pathology.

Brain-Derived Neurotrophic Factor (BDNF) Preserves the Functional Integrity of Neural Networks in the β-Amyloidopathy Model in vitro

“…In our work, we studied more prolonged effects caused by amyloid on neural network activity and identified a significant decrease. Our results are consistent with previous data from in vivo experiments and studies performed on brain slices obtained from different AD animal models, indicating that the early preclinical stages of AD are characterized by hyperactivation of neuronal activity, whereas the later stages are characterized by its suppression ( de Haan et al, 2017 ; Heggland et al, 2019 ).…”

Hippocampal hyperactivity in a rat model of Alzheimer’s disease

“…Indeed, APPtg rats exhibited an increased input resistance and reduced short-pulse rheobase at 6-9 months of age (Figure 4). Such electrophysiological changes have not been observed at earlier stages (age 3-4 months) in the same APPtg rat model (Heggland et al 2019;Qi et al 2014). In addition, the increased action potential half-width observed in this study further supports the view that intrinsic excitability changes in neurons contribute to neuronal hyperexcitability at early stages.…”

“…Indeed, APPtg rats exhibited an increased input resistance and reduced short‐pulse rheobase at 6–9 months of age (Figure 4). Such electrophysiological changes have not been observed at earlier stages (age 3–4 months) in the same APPtg rat model (Heggland et al 2019; Qi et al. 2014).…”

Hippocampal hyperactivity in a rat model of Alzheimer’s disease

“…3). Such electrophysiological changes have not been observed at earlier stages (age 3-4 months) in the same APPtg rat model 23,50 ,. In addition, the increased action potential half-width observed in the present study further supports the view that intrinsic excitability changes of neurons contribute to neuronal hyperexcitability at early stages.…”