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TitleCortical functional hyperconnectivity in a mouse model of depression and selective network effects of ketamine.
Publication TypeJournal Article
Year of Publication2017
AuthorsMcGirr, Alexander, Jeffrey LeDue, Allen W. Chan, Yicheng Xie, and Timothy H. Murphy
JournalBrain
Volume140
Issue8
Pagination2210-2225
Date Published2017 Aug 01
ISSN1460-2156
KeywordsAnimals, Antidepressive Agents, Aspartic Acid, Behavior, Animal, Cerebral Cortex, Depression, Disease Models, Animal, Dose-Response Relationship, Drug, Glutamic Acid, Ketamine, Male, Mice, Mice, Transgenic, Neural Pathways, Neurons, Social Behavior, Vesicular Glutamate Transport Proteins, Voltage-Sensitive Dye Imaging
Abstract

See Huang and Liston (doi:10.1093/awx166) for a scientific commentary on this article.Human depression is associated with glutamatergic dysfunction and alterations in resting state network activity. However, the indirect nature of human in vivo glutamate and activity assessments obscures mechanistic details. Using the chronic social defeat mouse model of depression, we determine how mesoscale glutamatergic networks are altered after chronic stress, and in response to the rapid acting antidepressant, ketamine. Transgenic mice (Ai85) expressing iGluSnFR (a recombinant protein sensor) permitted real-time in vivo selective characterization of extracellular glutamate and longitudinal imaging of mesoscale cortical glutamatergic functional circuits. Mice underwent chronic social defeat or a control condition, while spontaneous cortical activity was longitudinally sampled. After chronic social defeat, we observed network-wide glutamate functional hyperconnectivity in defeated animals, which was confirmed with voltage sensitive dye imaging in an independent cohort. Subanaesthetic ketamine has unique effects in defeated animals. Acutely, subanaesthetic ketamine induces large global cortical glutamate transients in defeated animals, and an elevated subanaesthetic dose resulted in sustained global increase in cortical glutamate. Local cortical inhibition of glutamate transporters in naïve mice given ketamine produced a similar extracellular glutamate phenotype, with both glutamate transients and a dose-dependent accumulation of glutamate. Twenty-four hours after ketamine, normalization of depressive-like behaviour in defeated animals was accompanied by reduced glutamate functional connectivity strength. Altered glutamate functional connectivity in this animal model confirms the central role of glutamate dynamics as well as network-wide changes after chronic stress and in response to ketamine.

DOI10.1093/brain/awx142
Alternate JournalBrain
PubMed ID28899017