Abstract
In Alzheimer's disease (AD), a decline in explicit memory is one of the earliest signs of disease and is associated with hippocampal dysfunction. Amyloid protein exerts a disruptive impact on neuronal function, but the specific effects on hippocampal network activity are not well known. In this study, fast voltage-sensitive dye imaging and extracellular and whole-cell electrophysiology were used on entorhinal cortical-hippocampal slice preparations to characterize hippocampal network activity in 12–16 month old female APPswe/PSEN1DeltaE9 (APdE9 mice) mice. Aged APdE9 mice exhibited profound disruptions in dentate gyrus circuit activation. High frequency stimulation of the perforant pathway in the dentate gyrus (DG) area of APdE9 mouse tissue evoked abnormally large field potential responses corresponding to the wider neural activation maps. Whole-cell patch clamp recordings of the identified inhibitory interneurons in the molecular layer of DG revealed that they fail to reliably fire action potentials. Taken together, abnormal DG excitability and an inhibitory neuron failure to generate action potentials are suggested to be important contributors to the underlying cellular mechanisms of early-stage Alzheimer's disease pathophysiology.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia in patients over the age of 65 that manifests as a progressive degenerative disorder in the central nervous system
While most published studies have used tissue from young animals for voltage-sensitive dye imaging (VSDI) imaging, in this study using concurrent electrophysiology and VSDI in aged brain tissue, we show that amyloid beta (Ab) expression results in broadly disruptive changes in hippocampal circuit and cell excitability, resulting in impaired short-term synaptic plasticity (STP) in the dentate gyrus
These findings suggest that the disruption in the inhibitory cell and network activity is likely to be an important contributor associated with the decline in spatial memory observed in APdE9 and similar hAPP mouse lines and, more broadly, these findings suggest that amyloid protein may directly contribute to the decline in shortterm memory associated with Alzheimer’s disease
Summary
Alzheimer’s disease (AD) is the most common form of dementia in patients over the age of 65 that manifests as a progressive degenerative disorder in the central nervous system. While most published studies have used tissue from young animals for VSDI imaging, in this study using concurrent electrophysiology and VSDI in aged brain tissue, we show that Ab expression results in broadly disruptive changes in hippocampal circuit and cell excitability, resulting in impaired short-term synaptic plasticity (STP) in the dentate gyrus These findings suggest that the disruption in the inhibitory cell and network activity is likely to be an important contributor associated with the decline in spatial memory observed in APdE9 and similar hAPP mouse lines and, more broadly, these findings suggest that amyloid protein may directly contribute to the decline in shortterm memory associated with Alzheimer’s disease
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