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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

A. Schematic representation of our working hypothesis on the mechanisms of action of IL-DBS. IL-DBS would activate glutamatergic neurons and increase glutamate concentration within the dorsal raphe. This would enhance the firing rate 5-HT neurons. Consequently, 5-HT release is enhanced in the hippocampus, influencing neurogenesis and synaptic plasticity. B. Astrocytes, by releasing gliotransmitters (such as glutamate and ATP), communicate with neurons at the synapse. Glutamate stimulates neuronal synaptic release and would contribute to the activation of post-synaptic receptors. ATP is rapidly hydrolyzed into adenosine (adeno), which would increase the stimulation of adenosine A1 receptors and, in turn, should result on a K+ channel-mediated reduction of the late hyperpolarization phase of action potentials (Sasaki et al., 2011). Ultimately, the resulting temporal shrinking of action potentials (AP width, in orange) may help the neuron to sustain the high frequency demand related to IL-DBS. Astrocytes also maintain the potassium homeostasis, by actively pumping K+ ions from the extracellular level thus preventing them to accumulate due to neuronal activity (in blue). A loss of astrocytes should therefore lead to an increase of extracellular [K+], which in turn would produce a depolarization of IL-PFC neuron membrane. This would facilitate basal pyramidal neuron activity, but, due to a “ceiling” phenomenon, would also likely impair the ability of pyramidal cells to respond to the phasic, high-frequency solicitation related to DBS. Actually, an increase of extracellular [K+] mimicked a glial lesion effect.
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f0030: A. Schematic representation of our working hypothesis on the mechanisms of action of IL-DBS. IL-DBS would activate glutamatergic neurons and increase glutamate concentration within the dorsal raphe. This would enhance the firing rate 5-HT neurons. Consequently, 5-HT release is enhanced in the hippocampus, influencing neurogenesis and synaptic plasticity. B. Astrocytes, by releasing gliotransmitters (such as glutamate and ATP), communicate with neurons at the synapse. Glutamate stimulates neuronal synaptic release and would contribute to the activation of post-synaptic receptors. ATP is rapidly hydrolyzed into adenosine (adeno), which would increase the stimulation of adenosine A1 receptors and, in turn, should result on a K+ channel-mediated reduction of the late hyperpolarization phase of action potentials (Sasaki et al., 2011). Ultimately, the resulting temporal shrinking of action potentials (AP width, in orange) may help the neuron to sustain the high frequency demand related to IL-DBS. Astrocytes also maintain the potassium homeostasis, by actively pumping K+ ions from the extracellular level thus preventing them to accumulate due to neuronal activity (in blue). A loss of astrocytes should therefore lead to an increase of extracellular [K+], which in turn would produce a depolarization of IL-PFC neuron membrane. This would facilitate basal pyramidal neuron activity, but, due to a “ceiling” phenomenon, would also likely impair the ability of pyramidal cells to respond to the phasic, high-frequency solicitation related to DBS. Actually, an increase of extracellular [K+] mimicked a glial lesion effect.

Mentions: The present study reveals that an ibotenic acid lesion within the IL-PFC prevented the antidepressant-like effect of DBS, showing that local neuronal population is implicated in the effects of the stimulation, and is not just “inactivated” as currently hypothesized. When activated by DBS, pyramidal neurons and their axons would release an augmented quantity of glutamate, leading to an over-activity of presumed 5-HT neurons within the DRN and an increase of 5-HT release in terminal areas (Fig. 6). Taken together, these results support the view that the antidepressant-like effect of a cortical stimulation might be mediated by both the activation of local neuronal population and the excitation of axons and passing fibers that would enhance, among others, 5-HT neurotransmission (A more detailed discussion on this “excitation vs inhibition theory” is provided in the Supplementary Material). Accordingly, we demonstrated that the antidepressant-like effect of IL-DBS was associated with an increase of slow oscillatory activities within the stimulated area, an effect prevented by local l-AAA infusion. A similar increase has been observed following ECT therapy, associated with an augmentation of IL-PFC synaptogenesis and gliogenesis (Bouckaert et al., 2014). Together, these findings raise the interesting hypothesis that fast-acting AD strategies share the common feature of re-enforcing intra-IL-PFC connections, which in turn may strengthen the positive modulation exerted by pyramidal neurons on their subcortical targets like the DRN. If so, the involvement of astrocytes in the AD effects of DBS, would not be surprising given their importance in the processes of synaptic plasticity and reinforcement.


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)

A. Schematic representation of our working hypothesis on the mechanisms of action of IL-DBS. IL-DBS would activate glutamatergic neurons and increase glutamate concentration within the dorsal raphe. This would enhance the firing rate 5-HT neurons. Consequently, 5-HT release is enhanced in the hippocampus, influencing neurogenesis and synaptic plasticity. B. Astrocytes, by releasing gliotransmitters (such as glutamate and ATP), communicate with neurons at the synapse. Glutamate stimulates neuronal synaptic release and would contribute to the activation of post-synaptic receptors. ATP is rapidly hydrolyzed into adenosine (adeno), which would increase the stimulation of adenosine A1 receptors and, in turn, should result on a K+ channel-mediated reduction of the late hyperpolarization phase of action potentials (Sasaki et al., 2011). Ultimately, the resulting temporal shrinking of action potentials (AP width, in orange) may help the neuron to sustain the high frequency demand related to IL-DBS. Astrocytes also maintain the potassium homeostasis, by actively pumping K+ ions from the extracellular level thus preventing them to accumulate due to neuronal activity (in blue). A loss of astrocytes should therefore lead to an increase of extracellular [K+], which in turn would produce a depolarization of IL-PFC neuron membrane. This would facilitate basal pyramidal neuron activity, but, due to a “ceiling” phenomenon, would also likely impair the ability of pyramidal cells to respond to the phasic, high-frequency solicitation related to DBS. Actually, an increase of extracellular [K+] mimicked a glial lesion effect.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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

f0030: A. Schematic representation of our working hypothesis on the mechanisms of action of IL-DBS. IL-DBS would activate glutamatergic neurons and increase glutamate concentration within the dorsal raphe. This would enhance the firing rate 5-HT neurons. Consequently, 5-HT release is enhanced in the hippocampus, influencing neurogenesis and synaptic plasticity. B. Astrocytes, by releasing gliotransmitters (such as glutamate and ATP), communicate with neurons at the synapse. Glutamate stimulates neuronal synaptic release and would contribute to the activation of post-synaptic receptors. ATP is rapidly hydrolyzed into adenosine (adeno), which would increase the stimulation of adenosine A1 receptors and, in turn, should result on a K+ channel-mediated reduction of the late hyperpolarization phase of action potentials (Sasaki et al., 2011). Ultimately, the resulting temporal shrinking of action potentials (AP width, in orange) may help the neuron to sustain the high frequency demand related to IL-DBS. Astrocytes also maintain the potassium homeostasis, by actively pumping K+ ions from the extracellular level thus preventing them to accumulate due to neuronal activity (in blue). A loss of astrocytes should therefore lead to an increase of extracellular [K+], which in turn would produce a depolarization of IL-PFC neuron membrane. This would facilitate basal pyramidal neuron activity, but, due to a “ceiling” phenomenon, would also likely impair the ability of pyramidal cells to respond to the phasic, high-frequency solicitation related to DBS. Actually, an increase of extracellular [K+] mimicked a glial lesion effect.
Mentions: The present study reveals that an ibotenic acid lesion within the IL-PFC prevented the antidepressant-like effect of DBS, showing that local neuronal population is implicated in the effects of the stimulation, and is not just “inactivated” as currently hypothesized. When activated by DBS, pyramidal neurons and their axons would release an augmented quantity of glutamate, leading to an over-activity of presumed 5-HT neurons within the DRN and an increase of 5-HT release in terminal areas (Fig. 6). Taken together, these results support the view that the antidepressant-like effect of a cortical stimulation might be mediated by both the activation of local neuronal population and the excitation of axons and passing fibers that would enhance, among others, 5-HT neurotransmission (A more detailed discussion on this “excitation vs inhibition theory” is provided in the Supplementary Material). Accordingly, we demonstrated that the antidepressant-like effect of IL-DBS was associated with an increase of slow oscillatory activities within the stimulated area, an effect prevented by local l-AAA infusion. A similar increase has been observed following ECT therapy, associated with an augmentation of IL-PFC synaptogenesis and gliogenesis (Bouckaert et al., 2014). Together, these findings raise the interesting hypothesis that fast-acting AD strategies share the common feature of re-enforcing intra-IL-PFC connections, which in turn may strengthen the positive modulation exerted by pyramidal neurons on their subcortical targets like the DRN. If so, the involvement of astrocytes in the AD effects of DBS, would not be surprising given their importance in the processes of synaptic plasticity and reinforcement.

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