Early Cellular Changes Related to Overproduction of Alzheimer's Amyloid-p Alter Synchronized Network Activity in Computational Model of Hippocampal Theta Rhythm Generation
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Hippocampal network dysfunction is thought to be an important component of early Alzheimer's disease (AD). Understanding hippocampal network dysfunction can lead to better understanding of the time course and progression of AD for the eventual development of reliable biomarkers and therapeutics. The hippocampal EEG pattern called theta rhythm has been recently observed to attenuate with age in transgenic mice expressing the early molecular phenomena associated with AD. Theta rhythm attenuation should be investigated at cell- and network-levels to understand early neurophysiological effects of amyloid deposition. We analyzed pyramidal cell population-level activity in a septo-hippocampal neural network based on Hodgkin-Huxley type ordinary differential equations that describe the dynamics of membrane conductances in the GENESIS neural simulation system. Results suggest neurophysiological changes in the hippocampal populations that contribute in unique ways to the observed age-dependent reduction of elicited theta power in local field potential. Changes suggested to contribute to theta rhythm attenuation include early CA1 pyramidal cell voltage-gated Na+ channel conductance decrease, voltage-gated K+ channel conductance increase, and selective oriens lacunosum-moleculare interneuron loss. These changes were also suggested to cause reduction in synchrony, increase in inter-spike interval duration and variability, and progressive violation of analytical network-rhythm stability requirements for post synaptic potential dynamics in pyramidal cell assemblies. The suggested cell- and population-level mechanisms of synchrony and rhythmicity loss could be important pathophysiological events in the time course of AD related to its characteristic amyloid plaque formation, hippocampal dysfunction, and cognitive decline.