Gliotransmission and adenosinergic modulation: insights from mammalian spinal motor networks

Acton, David; Miles, Gareth B.

doi:10.1152/jn.00230.2017

Cited by 11 publications

(23 citation statements)

References 203 publications

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“…There is converging evidence that stimulating astrocytes pharmacologically, or ablating astrocytes with gliotoxins, reveals purinergic-dependent, glial-derived modulation of the spinal cord locomotor CPG (Dale and Gilday, 1996;Dale, 1998;Brown and Dale, 2000;Witts et al, 2012Witts et al, , 2015Acton and Miles, 2015;Acevedo et al, 2016;Acton and Miles, 2017;Acton et al, 2018;Rivera-Oliver et al, 2018). Although astrocytes in other CNS regions demonstrate the ability to utilize other transmitters, such as glutamate or GABA (Malarkey and Parpura, 2008;Christensen et al, 2018); there is a paucity of evidence to suggest that other gliotransmitters are involved in the astrocytic control of the locomotor CPG.…”

Section: Discussionmentioning

confidence: 99%

“…Although astrocytes in other CNS regions demonstrate the ability to utilize other transmitters, such as glutamate or GABA (Malarkey and Parpura, 2008;Christensen et al, 2018); there is a paucity of evidence to suggest that other gliotransmitters are involved in the astrocytic control of the locomotor CPG. In previous studies, antagonists of purinergic signaling were sufficient to block all the astrocytic effects on the locomotor network (Acton and Miles, 2015;Witts et al, 2015;Acton and Miles, 2017;Acton et al, 2018). In this study, we have employed the pharmacogenetic DREADD approach to specifically target astrocytes and allow us to both excite and inhibit astrocytes.…”

Section: Discussionmentioning

confidence: 99%

“…Our data, therefore, support previously proposed mechanisms of glial-mediated modulation of the spinal locomotor CPG. The theory stands that astrocytes release ATP, which is subsequently converted to adenosine, which then acts at heteromeric dimers comprised of A1 adenosine and D1 dopaminergic receptors on CPG interneurons to reduce neuronal activity (Witts et al, 2015;Acton and Miles, 2017;Acton et al, 2018;Rivera-Oliver et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

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Bi-Directional Communication Between Neurons and Astrocytes Modulates Spinal Motor Circuits

Broadhead

Miles

2020

Front. Cell. Neurosci.

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Evidence suggests that astrocytes are not merely supportive cells in the nervous system but may actively participate in the control of neural circuits underlying cognition and behavior. In this study, we examined the role of astrocytes within the motor circuitry of the mammalian spinal cord. Pharmacogenetic manipulation of astrocytic activity in isolated spinal cord preparations obtained from neonatal mice revealed astrocytederived, adenosinergic modulation of the frequency of rhythmic output generated by the locomotor central pattern generator (CPG) network. Live Ca 2+ imaging demonstrated increased activity in astrocytes during locomotor-related output and in response to the direct stimulation of spinal neurons. Finally, astrocytes were found to respond to neuronally-derived glutamate in a metabotropic glutamate receptor 5 (mGluR5) dependent manner, which in turn drives astrocytic modulation of the locomotor network. Our work identifies bi-directional signaling mechanisms between neurons and astrocytes underlying modulatory feedback control of motor circuits, which may act to constrain network output within optimal ranges for movement. LAY SUMMARYWe have investigated how astrocytes, a type of supportive cell within the nervous system, may be directly involved in the control of movements, such as walking (locomotion). We found that astrocytes are active participants in the neural circuits of the mammalian spinal cord that control locomotion. The function of astrocytes within these networks appears to relate to the modulation of locomotor speed. We also identify the chemical signaling pathways involved in a modulatory feedback loop between astrocytes and neurons. Our findings suggest that this bi-directional communication between astrocytes and neurons may act to constrain spinal motor circuits within operational ranges for desired movements.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Bi-Directional Communication Between Neurons and Astrocytes Modulates Spinal Motor Circuits

Broadhead

Miles

2020

Front. Cell. Neurosci.

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“…Adenosine, which in many systems derives from the hydrolysis of ATP, is a potent modulator of spinal motor networks ( Acton and Miles 2017 ). Within isolated murine spinal cord ( Acevedo et al 2016 ; Acton and Miles 2015 , 2017 ; Witts et al 2012 ), adenosine derived from ATP acts at A 1 adenosine receptors (A 1 Rs) to reduce the frequency of ongoing locomotor-related bursting, a mechanism first described in Xenopus tadpoles ( Brown and Dale 2000 ; Dale and Gilday 1996 ). Neuromodulators may be released by neurons or astrocytes, which exhibit Ca 2+ -dependent release of so-called gliotransmitters ( Araque et al 1999 , 2014 ; Bazargani and Attwell 2016 ).…”

Section: Introductionmentioning

confidence: 99%

“…Neuromodulators may be released by neurons or astrocytes, which exhibit Ca 2+ -dependent release of so-called gliotransmitters ( Araque et al 1999 , 2014 ; Bazargani and Attwell 2016 ). Astrocytes are proposed as the principal source of neuromodulatory adenosine in the ventral horn, since adenosinergic modulation does not occur when astrocytes are pharmacologically ablated ( Acton and Miles 2015 , 2017 ; Witts et al 2012 ) and selective activation of the astrocytic receptor protease-activated receptor-1 (PAR1), a Gα q -linked G protein-coupled receptor, to stimulate Ca 2+ -dependent release of gliotransmitters, results in activation of A 1 Rs and modulation of neuronal activity ( Acton and Miles 2015 ; Carlsen and Perrier 2014 ).…”

Section: Introductionmentioning

confidence: 99%

Modulation of spinal motor networks by astrocyte-derived adenosine is dependent on D₁-like dopamine receptor signaling

Acton

Broadhead

Miles

2018

Journal of Neurophysiology

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Astrocytes modulate many neuronal networks, including spinal networks responsible for the generation of locomotor behavior. Astrocytic modulation of spinal motor circuits involves release of ATP from astrocytes, hydrolysis of ATP to adenosine, and subsequent activation of neuronal A1 adenosine receptors (A1Rs). The net effect of this pathway is a reduction in the frequency of locomotor-related activity. Recently, it was proposed that A1Rs modulate burst frequency by blocking the D1-like dopamine receptor (D1LR) signaling pathway; however, adenosine also modulates ventral horn circuits by dopamine-independent pathways. Here, we demonstrate that adenosine produced upon astrocytic stimulation modulates locomotor-related activity by counteracting the excitatory effects of D1LR signaling and does not act by previously described dopamine-independent pathways. In spinal cord preparations from postnatal mice, a D1LR agonist, SKF 38393, increased the frequency of locomotor-related bursting induced by 5-hydroxytryptamine and N-methyl-d-aspartate. Bath-applied adenosine reduced burst frequency only in the presence of SKF 38393, as did adenosine produced after activation of protease-activated receptor-1 to stimulate astrocytes. Furthermore, the A1R antagonist 8-cyclopentyl-1,3-dipropylxanthine enhanced burst frequency only in the presence of SKF 38393, indicating that endogenous adenosine produced by astrocytes during network activity also acts by modulating D1LR signaling. Finally, modulation of bursting by adenosine released upon stimulation of astrocytes was blocked by protein kinase inhibitor-(14–22) amide, a protein kinase A (PKA) inhibitor, consistent with A1R-mediated antagonism of the D1LR/adenylyl cyclase/PKA pathway. Together, these findings support a novel, astrocytic mechanism of metamodulation within the mammalian spinal cord, highlighting the complexity of the molecular interactions that specify motor output.NEW & NOTEWORTHY Astrocytes within the spinal cord produce adenosine during ongoing locomotor-related activity or when experimentally stimulated. Here, we show that adenosine derived from astrocytes acts at A1 receptors to inhibit a pathway by which D1-like receptors enhance the frequency of locomotor-related bursting. These data support a novel form of metamodulation within the mammalian spinal cord, enhancing our understanding of neuron-astrocyte interactions and their importance in shaping network activity.

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A norepinephrine‐dependent glial calcium wave travels in the spinal cord upon acoustovestibular stimuli

Orts-Del’Immagine

Dhanasekar

Lejeune

et al. 2021

Glia

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Although calcium waves have been widely observed in glial cells, their occurrence in vivo during behavior remains less understood. Here, we investigated the recruitment of glial cells in the hindbrain and spinal cord after acousto-vestibular (AV) stimuli triggering escape responses using in vivo population calcium imaging in larval zebrafish. We observed that gap-junction-coupled spinal glial network exhibits large and homogenous calcium increases that rose in the rostral spinal cord and propagated bi-directionally toward the spinal cord and toward the hindbrain. Spinal glial calcium waves were driven by the recruitment of neurons and in particular, of noradrenergic signaling acting through α-adrenergic receptors. Noradrenergic neurons of the medulla-oblongata (NE-MO) were revealed in the vicinity of where the calcium wave started. NE-MO were recruited upon AV stimulation and sent dense axonal projections in the rostro-lateral spinal cord, suggesting these cells could trigger the glial wave to propagate down the spinal cord. Altogether, our results revealed that a simple AV stimulation is sufficient to recruit noradrenergic neurons in the brainstem that trigger in the rostral spinal cord two massive glial calcium waves, one traveling caudally in the spinal cord and another rostrally into the hindbrain.

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Gliotransmission and adenosinergic modulation: insights from mammalian spinal motor networks

Cited by 11 publications

References 203 publications

Bi-Directional Communication Between Neurons and Astrocytes Modulates Spinal Motor Circuits

Bi-Directional Communication Between Neurons and Astrocytes Modulates Spinal Motor Circuits

Modulation of spinal motor networks by astrocyte-derived adenosine is dependent on D₁-like dopamine receptor signaling

A norepinephrine‐dependent glial calcium wave travels in the spinal cord upon acoustovestibular stimuli

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Gliotransmission and adenosinergic modulation: insights from mammalian spinal motor networks

Cited by 11 publications

References 203 publications

Bi-Directional Communication Between Neurons and Astrocytes Modulates Spinal Motor Circuits

Bi-Directional Communication Between Neurons and Astrocytes Modulates Spinal Motor Circuits

Modulation of spinal motor networks by astrocyte-derived adenosine is dependent on D1-like dopamine receptor signaling

A norepinephrine‐dependent glial calcium wave travels in the spinal cord upon acoustovestibular stimuli

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Modulation of spinal motor networks by astrocyte-derived adenosine is dependent on D₁-like dopamine receptor signaling