Journal Article

Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation

Murdock, M. H., Parekh, P. K., Bito, H., Milner, T. A., Alway, E. J., Moda-Sava, R. N., Lopez, K., Nellissen, L., Deisseroth, K., Rosenthal, D. L., Kasai, H., Witztum, J., Shaver, D. C., Liston, C., Huynh, T. N., Huang, B. S., Fetcho, R. N., Meng, Y., Grosenick, L.

2019

Overview

A better understanding of the mechanisms underlying the action of antidepressants is urgently needed. Moda-Sava et al. explored a possible mode of action for the drug ketamine, which has recently been shown to help patients recover from depression (see the Perspective by Beyeler). Ketamine rescued behavior in mice that was associated with depression-like phenotypes by selectively reversing stress-induced spine loss and restoring coordinated multicellular ensemble activity in prefrontal microcircuits. The initial induction of ketamine's antidepressant effect on mouse behavior occurred independently of effects on spine formation. Instead, synaptogenesis in the prefrontal region played a critical role in nourishing these effects over time. Interventions aimed at enhancing the survival of restored synapses may thus be useful for sustaining the behavioral effects of fast-acting antidepressants. Science , this issue p. eaat8078 ; see also p. 129 Spine formation in the prefrontal cortex is central to the long-term antidepressant effects of ketamine. The neurobiological mechanisms underlying the induction and remission of depressive episodes over time are not well understood. Through repeated longitudinal imaging of medial prefrontal microcircuits in the living brain, we found that prefrontal spinogenesis plays a critical role in sustaining specific antidepressant behavioral effects and maintaining long-term behavioral remission. Depression-related behavior was associated with targeted, branch-specific elimination of postsynaptic dendritic spines on prefrontal projection neurons. Antidepressant-dose ketamine reversed these effects by selectively rescuing eliminated spines and restoring coordinated activity in multicellular ensembles that predict motivated escape behavior. Prefrontal spinogenesis was required for the long-term maintenance of antidepressant effects on motivated escape behavior but not for their initial induction.

• Publisher: American Association for the Advancement of Science,The American Association for the Advancement of Science
• Subject: Animal models / Animals / Antidepressants / Antidepressive Agents - pharmacology / Antidepressive Agents - therapeutic use / Behavior / Brain / Correlation / Corticosterone - pharmacology / Dendritic spines / Dendritic Spines - drug effects / Dendritic Spines - pathology / Dendritic Spines - physiology / Dendritic structure / Depression (Psychology) / Depressive Disorder - chemically induced / Depressive Disorder - drug therapy / Depressive Disorder - physiopathology / Disease Models, Animal / Escape behavior / Escape Reaction - drug effects / Forecasting / Individual Differences / Ketamine / Ketamine - pharmacology / Ketamine - therapeutic use / Logical Thinking / Mathematical models / Medical imaging / Mental depression / Mental disorders / Mice / Mice, Inbred C57BL / Mice, Transgenic / Mode of action / Neurobiology / Neuroimaging / Neuronal Plasticity - drug effects / Neurons / Pharmacology / Phenotypes / Prefrontal cortex / Prefrontal Cortex - drug effects / Prefrontal Cortex - pathology / Prefrontal Cortex - physiopathology / Pyramidal cells / Remission / RESEARCH ARTICLE SUMMARY / Restoration / Signs and symptoms / Spine / Stress, Psychological - chemically induced / Stress, Psychological - physiopathology / Substrates / Survival / Synapses / Synapses - drug effects / Synapses - physiology / Synaptogenesis