QUANTITATIVE BIOLOGY SEMINAR<br>Cell and Network Level Changes Related to Overproduction of Alzheimer’s Amyloid-ß Cause Altered Synchronized Activity in Model of Hippocampal Theta Rhythm Generation

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 pathophysiology and progression of AD. Recent observation of reduced amplitude in the theta-frequency oscillation of total synaptic current in the hippocampus of AD mice models that overexpress the amyloid-ß peptide has not been explained in terms of cell and network level changes. This computational modeling study suggests cell and network level changes in the hippocampal populations that contribute to the observed age-dependent reduction of elicited theta power in local field potential that also imply subsequent theta frequency reduction and power normalization. Cell and population level mechanisms for this timecourse of altered synchronized activity are proposed in relation to previous analytical results. The representation of amyloid-induced changes in the model include CA1 pyramidal cell ion channel conductance changes and selective oriens lacunosum-moleculare interneuron loss.  Implemented in a biophysically realistic compartmental model network, these changes further implied altered synchrony, loss of period stability, and violation of analytical network synchrony requirements for post-synaptic potential and refractory behavior dynamics at firing times. The suggested cell and population level mechanisms of altered synchronized activity could be important pathophysiological events in the time course of AD related to its characteristic amyloid plaque formation, hippocampal dysfunction, and cognitive decline.