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Astroglial Control of the Antidepressant-Like Effects of Prefrontal Cortex Deep Brain Stimulation.

Etiévant A, Oosterhof C, Bétry C, Abrial E, Novo-Perez M, Rovera R, Scarna H, Devader C, Mazella J, Wegener G, Sánchez C, Dkhissi-Benyahya O, Gronfier C, Coizet V, Beaulieu JM, Blier P, Lucas G, Haddjeri N - EBioMedicine (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus

Effects of a local glial lesion on IL-DBS-induced enhancement of dentate gyrus mitogenesis. (A) Representative photomicrographs of dorsal and ventral hippocampi (magnification: in top × 10 and bottom × 40, enlarged view of boxed area in top) of sham and DBS-treated rats. BrdU-positive cells (black) were seen in granule cell layer (GCL). (B) IL-DBS increased mitogenesis in dorsal and ventral hippocampi (*p < 0.05, **p < 0.01 vs sham), an effect counteracted by l-AAA infusion (#p < 0.05, ###p < 0.001 vs DBS-treated rats). Numbers at the bottom of the columns represent the number of rats per group.
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f0010: Effects of a local glial lesion on IL-DBS-induced enhancement of dentate gyrus mitogenesis. (A) Representative photomicrographs of dorsal and ventral hippocampi (magnification: in top × 10 and bottom × 40, enlarged view of boxed area in top) of sham and DBS-treated rats. BrdU-positive cells (black) were seen in granule cell layer (GCL). (B) IL-DBS increased mitogenesis in dorsal and ventral hippocampi (*p < 0.05, **p < 0.01 vs sham), an effect counteracted by l-AAA infusion (#p < 0.05, ###p < 0.001 vs DBS-treated rats). Numbers at the bottom of the columns represent the number of rats per group.

Mentions: The neurogenic hypothesis of depression postulates that decreased production of new granule cells in the DG is linked to the pathophysiology of depression and that increased hippocampal neurogenesis is required for the behavioral effects of antidepressant treatment (Malberg et al., 2000, Santarelli et al., 2003). In the present study, the effect of 2 h IL-DBS (130 Hz, 150 μA bilaterally) on dorsal and ventral hippocampal mitogenesis was evaluated after BrdU labeling (Fig. 2A, Fig. S3). Remarkably, IL-DBS significantly increased mitogenesis in the dentate gyrus of dorsal and ventral hippocampi, an effect that was significantly prevented by a glial lesion within the stimulated area (Fig. 2B). Noteworthy, the glial lesion had no effect by itself on mitogenesis in the hippocampus, a result that correlated well with the lack of depression-like effect of the l-AAA infusion.


Astroglial Control of the Antidepressant-Like Effects of Prefrontal Cortex Deep Brain Stimulation.

Etiévant A, Oosterhof C, Bétry C, Abrial E, Novo-Perez M, Rovera R, Scarna H, Devader C, Mazella J, Wegener G, Sánchez C, Dkhissi-Benyahya O, Gronfier C, Coizet V, Beaulieu JM, Blier P, Lucas G, Haddjeri N - EBioMedicine (2015)

Effects of a local glial lesion on IL-DBS-induced enhancement of dentate gyrus mitogenesis. (A) Representative photomicrographs of dorsal and ventral hippocampi (magnification: in top × 10 and bottom × 40, enlarged view of boxed area in top) of sham and DBS-treated rats. BrdU-positive cells (black) were seen in granule cell layer (GCL). (B) IL-DBS increased mitogenesis in dorsal and ventral hippocampi (*p < 0.05, **p < 0.01 vs sham), an effect counteracted by l-AAA infusion (#p < 0.05, ###p < 0.001 vs DBS-treated rats). Numbers at the bottom of the columns represent the number of rats per group.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4563138&req=5

f0010: Effects of a local glial lesion on IL-DBS-induced enhancement of dentate gyrus mitogenesis. (A) Representative photomicrographs of dorsal and ventral hippocampi (magnification: in top × 10 and bottom × 40, enlarged view of boxed area in top) of sham and DBS-treated rats. BrdU-positive cells (black) were seen in granule cell layer (GCL). (B) IL-DBS increased mitogenesis in dorsal and ventral hippocampi (*p < 0.05, **p < 0.01 vs sham), an effect counteracted by l-AAA infusion (#p < 0.05, ###p < 0.001 vs DBS-treated rats). Numbers at the bottom of the columns represent the number of rats per group.
Mentions: The neurogenic hypothesis of depression postulates that decreased production of new granule cells in the DG is linked to the pathophysiology of depression and that increased hippocampal neurogenesis is required for the behavioral effects of antidepressant treatment (Malberg et al., 2000, Santarelli et al., 2003). In the present study, the effect of 2 h IL-DBS (130 Hz, 150 μA bilaterally) on dorsal and ventral hippocampal mitogenesis was evaluated after BrdU labeling (Fig. 2A, Fig. S3). Remarkably, IL-DBS significantly increased mitogenesis in the dentate gyrus of dorsal and ventral hippocampi, an effect that was significantly prevented by a glial lesion within the stimulated area (Fig. 2B). Noteworthy, the glial lesion had no effect by itself on mitogenesis in the hippocampus, a result that correlated well with the lack of depression-like effect of the l-AAA infusion.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus