Computer model of a theta-gamma dissociation in hippocampus

Theta-modulated gamma is commonly observed in hippocampus, with gamma localized at the peak of the theta. In aggregate, the neural activity underlying gamma generation will contribute to power in the theta band through low pass filtering. Injection of ketamine produces a surprising dissociation, decreasing theta activity despite increased gamma oscillation strength. Computer models of hippocampal CA3 were used to explore the theta/ gamma interplay and connect it to underlying pharmacological and dynamical influences. 1-5 compartment, 8-ion channel models of 800 pyramidal cells, 200 basket cells and 200 oriens-lacunosum moleculare (O-LM) cells were sparsely interconnected and driven by background synaptic bombardment. A rhythmic inhibition of O-LM cells was externally imposed in order to model the medial septum theta drive. The network was able to robustly produce theta-modulated gamma oscillations. AMPA receptor blockage produced a decrease in theta power in the simulated local field potential and disappearance of gamma oscillations in accordance with experimental results. This decrease in theta power was partially caused by the predicted loss of theta amplification from the gamma generated by basket cells and partially by the direct effects of decreased excitatory drive. By contrast, ketamine injection (modeled by decrease in NMDA conductance on O- LM cells), resulted in theta/gamma dissociation. Theta activity here decreased despite increased gamma oscillation strength. Theta rhythm was decreased because of lowered activity in the O-LM cells, whose reduced activity caused disinhibition of the pyramidal-basket-loop gamma generator resulted in the increase in gamma power. We were then able to recover the normal theta-gamma relationship by using current injection into O-LM cells, confirming that the ketamine action in the model was indeed mainly carried by lowering excitability of the O-LM cells rather than by a change in the activation dynamics. Coordination of activity through shared oscillation phase is thought to play a crucial role in perception and cognition. Ketamine produces psychosis in humans and is used as an animal model of schizophrenia. Theta-gamma dissociation may disrupt cognitive coordination in schizophrenia through an O-LM mediated mechanism that could be reversed through direct reactivation of O-LM cells.