RT Journal Article
SR Electronic
T1 Longitudinal effects of ketamine on dendritic architecture in vivo in the mouse medial frontal cortex
JF eneuro
JO eneuro
FD Society for Neuroscience
SP ENEURO.0133-15.2016
DO 10.1523/ENEURO.0133-15.2016
A1 Victoria Phoumthipphavong
A1 Florent Barthas
A1 Samantha Hassett
A1 Alex C. Kwan
YR 2016
UL http://www.eneuro.org/content/early/2016/03/22/ENEURO.0133-15.2016.abstract
AB A single subanesthetic dose of ketamine, an N-methyl-D-aspartate 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 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 changes of the spine elimination rate. A fraction of the new spines following ketamine injection was persistent, 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 re-balancing of synaptic inputs received by frontal cortical neurons.Significant Statement: A single dose of ketamine leads to fast-acting antidepressant effects, and thus understanding its mechanism of action would facilitate the development of new treatments for mood disorders. One potential mechanism is the remodeling of synaptic connections, because ketamine administration in rodents leads to a higher density of dendritic spines in the frontal cortex. Structural remodeling, however, is a dynamic process and the longitudinal effects of ketamine are poorly understood. In this study, we used cellular-resolution optical imaging methods to repeatedly visualize dendritic spines from the same set of neurons for >2 weeks in the mouse frontal cortex. The results are consistent with a model of action for ketamine involving the re-balancing of synaptic inputs in the frontal cortex.