title: Astroglial Control of the Antidepressant-Like Effects of Prefrontal Cortex Deep Brain Stimulation.
abstract: Although deep brain stimulation (DBS) shows promising efficacy as a therapy for intractable depression, the neurobiological bases underlying its therapeutic action remain largely unknown. The present study was aimed at characterizing the effects of infralimbic prefrontal cortex (IL-PFC) DBS on several pre-clinical markers of the antidepressant-like response and at investigating putative non-neuronal mechanism underlying DBS action. We found that DBS induced an antidepressant-like response that was prevented by IL-PFC neuronal lesion and by adenosine A1 receptor antagonists including caffeine. Moreover, high frequency DBS induced a rapid increase of hippocampal mitosis and reversed the effects of stress on hippocampal synaptic metaplasticity. In addition, DBS increased spontaneous IL-PFC low-frequency oscillations and both raphe 5-HT firing activity and synaptogenesis. Unambiguously, a local glial lesion counteracted all these neurobiological effects of DBS. Further in vivo electrophysiological results revealed that this astrocytic modulation of DBS involved adenosine A1 receptors and K(+) buffering system. Finally, a glial lesion within the site of stimulation failed to counteract the beneficial effects of low frequency (30 Hz) DBS. It is proposed that an unaltered neuronal-glial system constitutes a major prerequisite to optimize antidepressant DBS efficacy. It is also suggested that decreasing frequency could heighten antidepressant response of partial responders.
authors.affiliation: Stem Cell and Brain Research Institute, INSERM U846, 69500 Bron, France ; Université de Lyon, Université Lyon 1, 69373 Lyon, France ; Department of Psychiatry and Neurosciences, Faculty of Medicine, Laval University-IUSMQ, Québec City, Québec, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Etiévant
authors.affiliation: Institute of Mental Health Research, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Oosterhof
authors.affiliation: Stem Cell and Brain Research Institute, INSERM U846, 69500 Bron, France ; Université de Lyon, Université Lyon 1, 69373 Lyon, France.
authors.forename: C
authors.initials: C
authors.lastname: Bétry
authors.affiliation: Stem Cell and Brain Research Institute, INSERM U846, 69500 Bron, France ; Université de Lyon, Université Lyon 1, 69373 Lyon, France.
authors.forename: E
authors.initials: E
authors.lastname: Abrial
authors.affiliation: Stem Cell and Brain Research Institute, INSERM U846, 69500 Bron, France ; Université de Lyon, Université Lyon 1, 69373 Lyon, France.
authors.forename: M
authors.initials: M
authors.lastname: Novo-Perez
authors.affiliation: Stem Cell and Brain Research Institute, INSERM U846, 69500 Bron, France ; Université de Lyon, Université Lyon 1, 69373 Lyon, France.
authors.forename: R
authors.initials: R
authors.lastname: Rovera
authors.affiliation: Stem Cell and Brain Research Institute, INSERM U846, 69500 Bron, France ; Université de Lyon, Université Lyon 1, 69373 Lyon, France.
authors.forename: H
authors.initials: H
authors.lastname: Scarna
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, UMR6097, Université de Nice Sophia Antipolis, 06560 Valbonne, France.
authors.forename: C
authors.initials: C
authors.lastname: Devader
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, UMR6097, Université de Nice Sophia Antipolis, 06560 Valbonne, France.
authors.forename: J
authors.initials: J
authors.lastname: Mazella
authors.affiliation: Department of Clinical Medicine, Translational Neuropsychiatry Unit, Aarhus University, Skovagervej 2, DK-8240 Risskov, Denmark.
authors.forename: G
authors.initials: G
authors.lastname: Wegener
authors.affiliation: Neuropharmacology, Lundbeck Research USA, Paramus, NJ, USA.
authors.forename: C
authors.initials: C
authors.lastname: Sánchez
authors.affiliation: Stem Cell and Brain Research Institute, INSERM U846, 69500 Bron, France ; Université de Lyon, Université Lyon 1, 69373 Lyon, France.
authors.forename: O
authors.initials: O
authors.lastname: Dkhissi-Benyahya
authors.affiliation: Stem Cell and Brain Research Institute, INSERM U846, 69500 Bron, France ; Université de Lyon, Université Lyon 1, 69373 Lyon, France.
authors.forename: C
authors.initials: C
authors.lastname: Gronfier
authors.affiliation: INSERM U836, GIN, Univ. Grenoble Alpes, F-38000 Grenoble, France.
authors.forename: V
authors.initials: V
authors.lastname: Coizet
authors.affiliation: Department of Psychiatry and Neurosciences, Faculty of Medicine, Laval University-IUSMQ, Québec City, Québec, Canada.
authors.forename: J M
authors.initials: JM
authors.lastname: Beaulieu
authors.affiliation: Institute of Mental Health Research, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Blier
authors.affiliation: Stem Cell and Brain Research Institute, INSERM U846, 69500 Bron, France ; Université de Lyon, Université Lyon 1, 69373 Lyon, France ; Institut François Magendie, INSERM U862, Université de Bordeaux, 33077 Bordeaux, France.
authors.forename: G
authors.initials: G
authors.lastname: Lucas
authors.affiliation: Stem Cell and Brain Research Institute, INSERM U846, 69500 Bron, France ; Université de Lyon, Université Lyon 1, 69373 Lyon, France.
authors.forename: N
authors.initials: N
authors.lastname: Haddjeri
mesh_terms: D000818:Animals; D001253:Astrocytes; D046690:Deep Brain Stimulation; D003863:Depression / Q000503:physiopathology* / Q000628:therapy*; D008297:Male; D017397:Prefrontal Cortex / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley
keywords: Astrocytes; DBS, deep brain stimulation; Deep brain stimulation; Depression; HFS, high frequency stimulation; IL-PFC, infralimbic prefrontal cortex; LFS, low frequency stimulation; PCPA, 4-chloro-dl-phenylalanine methyl ester; Prefrontal cortex; Serotonin; fEPSP, field excitatory post-synaptic potential; l-AAA, l-alpha-aminoadipic acid