Regional alterations of parvalbumin interneurons in human App knock-in mouse model of Alzheimer’s disease pathology

Early-stage Alzheimer's disease 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 Alzheimer's disease pathology on different neuron subtypes in both the entorhinal cortex, a region known to be affected early in Alzheimer's disease, and the primary visual cortex, a relatively unaffected region. 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 2 month old amyloid precursor protein knock-in (APP-KI) mice. In entorhinal cortex, amyloid overproduction resulted in parvalbumin 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 exhibit selective functional alterations in an early APP-driven state.