Global excitatory synchrony: Ketamine induces global common-mode excitatory network oscillation by decoupling key interneurons

Abstract

Ketamine is a dissociative anesthetic used in subanesthetic doses with analgesic and anti-depressive properties. However, its mechanistic effects on neuronal signaling and circuit function remain underexplored. We address this shortcoming by employing multi-neuronal imaging in the simple nematode C. elegans that allows measurement of neuron activity across the animals entire head with single-cell resolution. Neuronal imaging during low dose ketamine induction reveals two distinct phases: an early/low dose state of hyperactive synchronized dynamics and late/higher dose state of system disorganization and spastic microscale motion. Specifically examining the activity of the NMDA-receptive interneuron AVA, we find it decouples from the system under low dose ketamine. These results are consistent with the clinical hypothesis that ketamine causes neuronal disinhibition through suppression of key inhibitory interneurons. We identify functional differences between low and high dose activity dynamics and elucidate a mechanism of action of ketamine in a complete, intact nervous system.