Mechanisms of Sustained Increases in γ Power Post-Ketamine in a Computational Model of the Hippocampal CA3: Implications for Ketamine’s Antidepressant Mechanism of Action

Subanaesthetic doses of ketamine increase [Formula: see text] oscillation power in neural activity measured using electroencephalography (EEG), and this effect lasts several hours after ketamine administration. The mechanisms underlying this effect are unknown. Using a computational model of the hippocampal cornu ammonis 3 (CA3) network, which is known to reproduce ketamine’s acute effects on [Formula: see text] power, we simulated the plasticity of glutamatergic synapses in pyramidal cells to test which of the following hypotheses would best explain this sustained [Formula: see text] power: the direct inhibition hypothesis, which proposes that increased [Formula: see text] power post-ketamine administration may be caused by the potentiation of recurrent collateral synapses, and the disinhibition hypothesis, which proposes that potentiation affects synapses from both recurrent and external inputs. Our results suggest that the strengthening of external connections to pyramidal cells is able to account for the sustained [Formula: see text] power increase observed post-ketamine by increasing the overall activity of and synchrony between pyramidal cells. The strengthening of recurrent pyramidal weights, however, would cause an additional phase shifted voltage increase that ultimately reduces [Formula: see text] power due to partial cancellation. Our results therefore favor the disinhibition hypothesis for explaining sustained [Formula: see text] oscillations after ketamine administration.