Midazolam and atropine alter theta oscillations in the hippocampal CA1 region by modulating both the somatic and distal dendritic dipoles.

Theta (4-12 Hz) oscillations in the hippocampus play an important role in learning and memory. They are altered by a wide variety of drugs that impair memory, and these effects may underlie or contribute to drug-induced amnesia. However, the network mechanisms linking drug actions with changes in memory formation remain poorly defined. Here, we used a multisite linear electrode array to measure local field potentials simultaneously across the CA1 layers of the hippocampus during active exploration, and employed current source density analysis and computational modeling to investigate how midazolam and atropine-two amnestic drugs that are used clinically and experimentally-change the relative timing and strength of the drivers of θ-oscillations. We found that two dipoles are present, with active inputs that are centered at the soma and the distal apical dendrite and passive return pathways that overlap in the mid-apical dendrite. Both drugs shifted the position of the phase reversal in the local field potential that occurred in the mid-apical dendritic region, but in opposite directions, by changing the strength of the dendritic pole, without altering the somatic pole or relative timing. Computational modeling showed that this constellation of changes, as well as an additional effect on a variably present mid-apical pole, could be produced by simultaneous changes in the active somatic and distal dendritic inputs. These network-level changes, produced by two amnestic drugs that target different types of receptors, may thus serve as a common basis for impaired memory encoding.