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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 glial lesion on IL-DBS-induced changes in hippocampal synaptic metaplasticity. (A) Inset: schematic representation of the experimental protocol showing a stimulating and a recording electrode in the hippocampus and a DBS electrode in the IL-PFC. Time-course responses illustrate changes induced by DBS and glial lesions in naïve rats. (B) Time-course responses in stressed rats illustrating the effects of glial lesion on DBS modulation of synaptic plasticity. Insets show typical field EPSPs recorded before and after low and high frequency stimulations; calibration vertical bar, 0.5 mV; horizontal bar, 5 ms. (C) Area Under the Curve (AUC) histograms illustrate changes induced after LFS or HFS by IL-DBS and/or glial lesion in sham and stressed rats. (D) AUC histograms illustrate changes induced after LFS or HFS by IL-DBS and/or PCPA injections in naive rats. Numbers at the bottom of the columns represent the number of rats per group (*p < 0.05 **p < 0.01 and ***p < 0.001 vs naïve sham. #p < 0.05, ##p < 0.01 and ###p < 0.01 vs DBS-treated group, αp < 0.05 vs stress group).
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f0015: Effects of a glial lesion on IL-DBS-induced changes in hippocampal synaptic metaplasticity. (A) Inset: schematic representation of the experimental protocol showing a stimulating and a recording electrode in the hippocampus and a DBS electrode in the IL-PFC. Time-course responses illustrate changes induced by DBS and glial lesions in naïve rats. (B) Time-course responses in stressed rats illustrating the effects of glial lesion on DBS modulation of synaptic plasticity. Insets show typical field EPSPs recorded before and after low and high frequency stimulations; calibration vertical bar, 0.5 mV; horizontal bar, 5 ms. (C) Area Under the Curve (AUC) histograms illustrate changes induced after LFS or HFS by IL-DBS and/or glial lesion in sham and stressed rats. (D) AUC histograms illustrate changes induced after LFS or HFS by IL-DBS and/or PCPA injections in naive rats. Numbers at the bottom of the columns represent the number of rats per group (*p < 0.05 **p < 0.01 and ***p < 0.001 vs naïve sham. #p < 0.05, ##p < 0.01 and ###p < 0.01 vs DBS-treated group, αp < 0.05 vs stress group).

Mentions: Hippocampal synaptic plasticity is considered as a reliable preclinical parameter allowing the characterization of antidepressant-induced changes in the molecular and physiological events that underpin the regulation of synaptic connectivity related to their therapeutic efficacy (Berton and Nestler, 2006, Pittenger and Duman, 2008). Hence, the modulation of hippocampus synaptic metaplasticity by IL-DBS and glial lesion was examined in vivo by application of low and high frequency stimulations (LFS and HFS) on Schaffer's collateral pathway to induce long-term depression (LTD) or long-term potentiation (LTP), respectively, in hippocampal CA1 area (Fig. 3A inset).


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 glial lesion on IL-DBS-induced changes in hippocampal synaptic metaplasticity. (A) Inset: schematic representation of the experimental protocol showing a stimulating and a recording electrode in the hippocampus and a DBS electrode in the IL-PFC. Time-course responses illustrate changes induced by DBS and glial lesions in naïve rats. (B) Time-course responses in stressed rats illustrating the effects of glial lesion on DBS modulation of synaptic plasticity. Insets show typical field EPSPs recorded before and after low and high frequency stimulations; calibration vertical bar, 0.5 mV; horizontal bar, 5 ms. (C) Area Under the Curve (AUC) histograms illustrate changes induced after LFS or HFS by IL-DBS and/or glial lesion in sham and stressed rats. (D) AUC histograms illustrate changes induced after LFS or HFS by IL-DBS and/or PCPA injections in naive rats. Numbers at the bottom of the columns represent the number of rats per group (*p < 0.05 **p < 0.01 and ***p < 0.001 vs naïve sham. #p < 0.05, ##p < 0.01 and ###p < 0.01 vs DBS-treated group, αp < 0.05 vs stress group).
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f0015: Effects of a glial lesion on IL-DBS-induced changes in hippocampal synaptic metaplasticity. (A) Inset: schematic representation of the experimental protocol showing a stimulating and a recording electrode in the hippocampus and a DBS electrode in the IL-PFC. Time-course responses illustrate changes induced by DBS and glial lesions in naïve rats. (B) Time-course responses in stressed rats illustrating the effects of glial lesion on DBS modulation of synaptic plasticity. Insets show typical field EPSPs recorded before and after low and high frequency stimulations; calibration vertical bar, 0.5 mV; horizontal bar, 5 ms. (C) Area Under the Curve (AUC) histograms illustrate changes induced after LFS or HFS by IL-DBS and/or glial lesion in sham and stressed rats. (D) AUC histograms illustrate changes induced after LFS or HFS by IL-DBS and/or PCPA injections in naive rats. Numbers at the bottom of the columns represent the number of rats per group (*p < 0.05 **p < 0.01 and ***p < 0.001 vs naïve sham. #p < 0.05, ##p < 0.01 and ###p < 0.01 vs DBS-treated group, αp < 0.05 vs stress group).
Mentions: Hippocampal synaptic plasticity is considered as a reliable preclinical parameter allowing the characterization of antidepressant-induced changes in the molecular and physiological events that underpin the regulation of synaptic connectivity related to their therapeutic efficacy (Berton and Nestler, 2006, Pittenger and Duman, 2008). Hence, the modulation of hippocampus synaptic metaplasticity by IL-DBS and glial lesion was examined in vivo by application of low and high frequency stimulations (LFS and HFS) on Schaffer's collateral pathway to induce long-term depression (LTD) or long-term potentiation (LTP), respectively, in hippocampal CA1 area (Fig. 3A inset).

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