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

• Published in: Science (American Association for the Advancement of Science) Vol. 364; no. 6436
• Main Authors: Moda-Sava, R N, Murdock, M H, Parekh, P K, Fetcho, R N, Huang, B S, Huynh, T N, Witztum, J, Shaver, D C, Rosenthal, D L, Alway, E J, Lopez, K, Meng, Y, Nellissen, L, Grosenick, L, Milner, T A, Deisseroth, K, Bito, H, Kasai, H, Liston, C
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 12.04.2019
• Subjects: 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; Restoration; Signs and symptoms; Spine; Stress, Psychological - chemically induced; Stress, Psychological - physiopathology; Substrates; Survival; Synapses; Synapses - drug effects; Synapses - physiology; Synaptogenesis
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.aat8078

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.