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 beta (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 in the McGill-R-Thy1-APP transgenic rat model, using whole-cell patch clamp recordings and voltage-sensitive dye imaging 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. Whereas the electrophysiological properties of fan cells were unaltered, stellate cells were more excitable in transgenic than in control rats. Stimulation in the dentate gyrus resulted in comparable patterns in both groups at 3 and 9 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 entorhinal cortex. 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.

Significance statement The hippocampal region, essential for episodic memory, is affected in the early stages of Alzheimer’s disease. Here, we use the McGill-R-Thy1-APP transgenic rat model to study the effects of Aβ pathology on networks and single cells in the hippocampal region. In young animals, we observed widespread intracellular Aβ accumulation, which later progressed to extracellular plaques. However, the in vitro physiology was largely unaltered, with only changes in single cell excitability of stellate cells in layer II of MEC and network activation patterns in dentate gyrus. Thus, these two components of the entorhinal-hippocampal network emerge as potentially more vulnerable in the context of Aβ pathology.