Figure 3.

Pathologically elevated Aβ elicits abnormal patterns of neuronal activity in circuits and in wider networks in Alzheimer disease–related mouse models. (A) Neuronal circuits are formed by synaptic interactions between excitatory and inhibitory cells. Aβ might differentially affect excitatory (+) and inhibitory (−) synapses and cells, producing complex imbalances in circuit and network activity. (B) At the network level, high levels of Aβ increase network synchrony and elicit epileptiform activity, as illustrated here in EEG recordings from the left and right parietal cortex (LPC and RPC, respectively) of nontransgenic (NTG) controls (blue) and hAPP transgenic mice from line J20 (red). (C) hAPP mice show fluctuations in the neuronal expression of synaptic activity–dependent genes, suggesting network instability. Top: Compared with NTG controls (left), hAPP-J20 mice show abnormally low (middle) or high (right) Arc expression in granule cells of the dentate gyrus (adapted, with permission, from Palop et al. 2005, 2007). Percentages indicate the proportion of mice showing the different patterns of Arc expression. Such marked increases in Arc expression are typically caused by seizure activity. Bottom: Interpretive diagram. Marked fluctuations in neuronal activity may directly impair cognition by reducing the time the network spends in activity patterns that promote normal cognitive functions. (D) In cortical circuits of mice monitored in vivo by calcium imaging, most neurons in NTG controls (blue traces) have an intermediate level of activity, whereas many neurons in hAPP/PS1 transgenic mice with high Aβ levels (red traces) are either hypoactive (top) or hyperactive (bottom). (Adapted, with permission, from Palop and Mucke 2010.)