Amyloid-β alters ongoing neuronal activity and excitability in the frontal cortex

The effects of amyloid-β on the activity and excitability of individual neurons in the early and advanced stages of the pathological progression of Alzheimer's disease remain unknown. We used in vivo intracellular recordings to measure the ongoing and evoked activity of pyramidal neurons in the frontal cortex of APPswe/PS1dE9 transgenic mice and age-matched nontransgenic littermate controls. Evoked excitability was altered in both transgenic groups: neurons in young transgenic mice displayed hypoexcitability, whereas those in older transgenic mice displayed hyperexcitability, suggesting changes in intrinsic electrical properties of the neurons. However, the ongoing activity of neurons in both young and old transgenic groups showed signs of hyperexcitability in the depolarized state of the membrane potential. The membrane potential of neurons in old transgenic mice had an increased tendency to fail to transition to the depolarized state, and the depolarized states had shorter durations on average than did controls. This suggests a combination of both intrinsic electrical and synaptic dysfunctions as mechanisms for activity changes at later stages of the neuropathological progression.