Regional susceptibility of PV interneurons in an hAPP-KI mouse model of Alzheimer's disease pathology

Abstract

Early-stage Alzheimers pathology correlates with disrupted neuronal excitability, which can drive network and cognitive dysfunction even prior to neurodegeneration. However, the emergence and extent of these changes may vary by brain region and cell types situated in those regions. Here we aimed to investigate the effects of AD pathology on different neuron subtypes in both the entorhinal cortex, a region with enhanced pathology in early AD, and the primary visual cortex, a relatively unaffected region in early-stage AD. We designed and employed a semi-automated patch clamp electrophysiology apparatus to record from fast-spiking parvalbumin interneurons and excitatory neurons in these regions, recording from over 150 cells in young adult APP-KI mice. In entorhinal cortex, amyloid overproduction resulted in PV interneuron hypoexcitability, whereas excitatory neurons were concurrently hyperexcitable. Conversely, neurons of either subclass were largely unaffected in the visual cortex. Together, these findings suggest that fast-spiking parvalbumin interneurons in the entorhinal cortex, but not in the visual cortex, play an integral role in AD progression.