Longitudinal Effects of Ketamine on Dendritic ArchitectureIn Vivoin the Mouse Medial Frontal Cortex

A single low dose of ketamine, an NMDA receptor antagonist, produces fast-acting antidepressant effects. In mice, a single injection of ketamine increased dendritic spine density in the medial frontal cortex for up to two weeks compared to saline-injected controls. This prolonged increase was driven by a higher rate of new spine formation, not by changes in spine elimination. Some new spines persisted, indicating functional synapses. In a few cases, distal apical tuft branches retracted the day after ketamine administration. These findings suggest that ketamine causes immediate removal of some dendritic inputs and gradual addition of others, consistent with a rebalancing of synaptic inputs onto frontal cortical neurons.

Study at a glance

Abstract

A single subanesthetic dose of ketamine, an NMDA receptor antagonist, leads to fast-acting antidepressant effects. In rodent models, systemic ketamine is associated with higher dendritic spine density in the prefrontal cortex, reflecting structural remodeling that may underlie the behavioral changes. However, turnover of dendritic spines is a dynamic process in vivo, and the longitudinal effects of ketamine on structural plasticity remain unclear. The purpose of the current study is to use subcellular resolution optical imaging to determine the time course of dendritic alterations in vivo following systemic ketamine administration in mice. We used two-photon microscopy to visualize repeatedly the same set of dendritic branches in the mouse medial frontal cortex (MFC) before and after a single injection of ketamine or saline. Compared to controls, ketamine-injected mice had higher dendritic spine density in MFC for up to 2 weeks. This prolonged increase in spine density was driven by an elevated spine formation rate, and not by changes in the spine elimination rate. A fraction of the new spines following ketamine injection was persistent, which is indicative of functional synapses. In a few cases, we also observed retraction of distal apical tuft branches on the day immediately after ketamine administration. These results indicate that following systemic ketamine administration, certain dendritic inputs in MFC are removed immediately, while others are added gradually. These dynamic structural modifications are consistent with a model of ketamine action in which the net effect is a rebalancing of synaptic inputs received by frontal cortical neurons.