Ketamine evoked disruption of entorhinal and hippocampal spatial maps

Ketamine, used as a fast-acting anesthetic and antidepressant, causes spatial cognition side effects such as out-of-body experiences and spatial memory impairments, but the underlying neural mechanisms were unclear. In mice navigating virtual and real environments, ketamine acutely disrupted and then re-organized spatial representations in the medial entorhinal cortex, increasing excitatory neuron firing rates and degrading temporal coordination between cell pairs. In the hippocampus, neurons encoding the animal's position were suppressed after ketamine. These findings suggest that disruption of spatial coding in the entorhinal-hippocampal circuit may underlie ketamine-induced changes in spatial cognition.

Study at a glance

Abstract

Ketamine, a rapid-acting anesthetic and acute antidepressant, carries undesirable spatial cognition side effects including out-of-body experiences and spatial memory impairments. The neural substrates that underlie these alterations in spatial cognition however, remain incompletely understood. Here, we used electrophysiology and calcium imaging to examine ketamine’s impacts on the medial entorhinal cortex and hippocampus, which contain neurons that encode an animal’s spatial position, as mice navigated virtual reality and real world environments. Ketamine induced an acute disruption and long-term re-organization of entorhinal spatial representations. This acute ketamine-induced disruption reflected increased excitatory neuron firing rates and degradation of cell-pair temporal firing rate relationships. In the reciprocally connected hippocampus, the activity of neurons that encode the position of the animal was suppressed after ketamine administration. Together, these findings point to disruption in the spatial coding properties of the entorhinal-hippocampal circuit as a potential neural substrate for ketamine-induced changes in spatial cognition.