Neuromodulation via Conditional Release of Endocannabinoids in the Spinal Locomotor Network

Kettunen, Petronella; Kyriakatos, Alexandros; Hallén, Kristofer; Manira, Abdeljabbar El

doi:10.1016/j.neuron.2004.12.022

Cited by 63 publications

(76 citation statements)

References 48 publications

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“…Endocannabinoids released by activation of mGluR1 mediate the long-term potentiation We showed previously that activation of group 1 mGluRs induces release of endocannabinoids from locomotor network neurons (Kettunen et al, 2005). To test whether the long-term potentiation of the locomotor frequency induced by activation of mGluR1 also involves release of endocannabinoids within the locomotor circuitry, the effect of DHPG was tested in preparations preincubated with the cannabinoid receptor antagonist AM-251 (1 M).…”

Section: Resultsmentioning

confidence: 99%

“…In this study, we have examined the role of endocannabinoids and nitric oxide in mediating long-term plasticity of the locomotor activity and have analyzed the synaptic mechanisms responsible. We have used the lamprey spinal cord in which endocannabinoids, released by activation of metabotropic glutamate receptor 1 (mGluR1), act as an intrinsic modulator (Kettunen et al, 2005). In the lamprey (Buchanan, 1982;Buchanan and Grillner, 1987;Grillner, 2003), as in Xenopus tadpoles (Dale, 1985;Dale and Roberts, 1985), the basic organization of the spinal locomotor circuit has been characterized.…”

Section: Introductionmentioning

confidence: 99%

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Long-Term Plasticity of the Spinal Locomotor Circuitry Mediated by Endocannabinoid and Nitric Oxide Signaling

Kyriakatos¹,

Manira²

2007

J. Neurosci.

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Retrograde signaling by endocannabinoids is known to induce short-and long-term synaptic plasticity, but the significance of this modulation for the activity of neural networks underlying motor behavior is largely unclear. Here, we used the isolated lamprey spinal cord to show that endocannabinoids released by activation of metabotropic glutamate receptor 1 (mGluR1) induce long-term synaptic plasticity during an ongoing locomotor rhythm and how this is translated onto the integrated activity of the spinal circuitry. A brief activation of mGluR1 induces a long-term increase in the locomotor frequency that is mediated by a concomitant long-term depression of midcycle reciprocal inhibition and long-term potentiation of ipsilateral synaptic excitation arising from locomotor circuit interneurons. Blockade of cannabinoid receptors with AM251 prevented the mGluR1-mediated long-term plasticity of both inhibitory and excitatory synaptic transmission, as well as that of the locomotor activity. Similarly, inhibition of nitric oxide signaling blocked the mGluR1-mediated long-term plasticity. These results show that the locomotor circuitry is endowed with a "memory" capacity mediated by a long-term shift in the balance between synaptic inhibition and excitation. This is triggered by activation of mGluR1 and requires subsequent endocannabinoid and nitric oxide signaling.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Long-Term Plasticity of the Spinal Locomotor Circuitry Mediated by Endocannabinoid and Nitric Oxide Signaling

Kyriakatos¹,

Manira²

2007

J. Neurosci.

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“…The frequencies obtained with stimulation are comparable to those recorded in freely swimming animals. During NMDAinduced swimming activity, additional input from descending fibers produces long-term potentiation of the burst frequency (Kettunen et al, 2005;Kyriakatos and El Manira, 2007;El Manira and Kyriakatos, 2010). The experimental approach used to induce fictive swimming in vitro bears similarities with the way the spinal locomotor networks are activated in vivo and are therefore more physiological than the use of pharmacology.…”

Section: Discussionmentioning

confidence: 99%

Initiation of Locomotion in Adult Zebrafish

Kyriakatos

Mahmood²,

Ausborn³

et al. 2011

Journal of Neuroscience

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Motor behavior is generated by specific neural circuits. Those producing locomotion are located in the spinal cord, and their activation depends on descending inputs from the brain or on sensory inputs. In this study, we have used an in vitro brainstem-spinal cord preparation from adult zebrafish to localize a region where stimulation of descending inputs can induce sustained locomotor activity. We show that a brief stimulation of descending inputs at the junction between the brainstem and spinal cord induces long-lasting swimming activity. The swimming frequencies induced are remarkably similar to those observed in freely moving adult fish, arguing that the induced locomotor episode is highly physiological. The motor pattern is mediated by activation of ionotropic glutamate and glycine receptors in the spinal cord and is not the result of synaptic interactions between neurons at the site of the stimulation in the brainstem. We also compared the activity of motoneurons during locomotor activity induced by electrical stimulation of descending inputs and by exogenously applied NMDA. Prolonged NMDA application changes the shape of the synaptic drive and action potentials in motoneurons. When escape activity occurs, the swimming activity in the intact zebrafish was interrupted and some of the motoneurons involved became inhibited in vitro. Thus, the descending inputs seem to act as a switch to turn on the activity of the spinal locomotor network in the caudal spinal cord. We propose that recurrent synaptic activity within the spinal locomotor circuits can transform a brief input into a well coordinated and long-lasting swimming pattern.

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“…Although a long-lasting effect of NO donors on the locomotor frequency was seen in some preparations, this was not always the case. It could be that the mGluR-mediated longterm potentiation requires both NO and other modulators, such as endocannabinoids (Kettunen et al, 2005). The shift in balance between inhibition and excitation during locomotion induced by NO is reminiscent of that induced by mGluR1 and by endocannabinoids, suggesting that similar synaptic targets are modulated by different modulatory pathways (El Manira et al, 2002;LeBeau et al, 2005;El Manira et al, 2008).…”

Section: Mechanisms Of No-mediated Modulationmentioning

confidence: 99%

Nitric Oxide Potentiation of Locomotor Activity in the Spinal Cord of the Lamprey

Kyriakatos¹,

Molinari²,

Mahmood³

et al. 2009

J. Neurosci.

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To understand the intrinsic operation of spinal networks generating locomotion, we need to not only characterize the constituent neurons and their connectivity, but also determine the role of intrinsic modulation in shaping the final motor output. We have focused on the effects of nitric oxide (NO) on the locomotor frequency and the underlying synaptic mechanisms in the lamprey spinal cord. To identify the source of NO, we used NADPH-diaphorase histochemistry and nNOS immunocytochemistry. Gray matter and sensory neurons were positively labeled using both methods. Preparations preincubated with NO synthase inhibitors displayed slower locomotor frequency that increased upon washout of the inhibitors, suggesting that NO is an endogenous neuromodulator in the spinal cord. Application of NO donors increased the locomotor frequency that was blocked by an NO scavenger and partially reduced by an inhibitor of sGC. To analyze the synaptic modulation underlying the NO-induced increase of the locomotor frequency we performed intracellular recordings from motoneurons and interneurons. The NO-induced increase in locomotor frequency was associated with a decrease in the midcycle inhibition and an increase in on-cycle excitation. To determine the site of action of NO, we examined the effect of NO donors on miniature PSCs. NO increased both the frequency and amplitude of mEPSCs while it only decreased the frequency of mIPSCs, suggesting the increased excitation is mediated by both presynaptic and postsynaptic mechanisms, while the decrease in inhibition involves only presynaptic mechanisms. Our results demonstrate a significant role of NO in adult vertebrate motor control which, via modulation of both excitatory and inhibitory transmission, increases the locomotor burst frequency.

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Neuromodulation via Conditional Release of Endocannabinoids in the Spinal Locomotor Network

Cited by 63 publications

References 48 publications

Long-Term Plasticity of the Spinal Locomotor Circuitry Mediated by Endocannabinoid and Nitric Oxide Signaling

Long-Term Plasticity of the Spinal Locomotor Circuitry Mediated by Endocannabinoid and Nitric Oxide Signaling

Initiation of Locomotion in Adult Zebrafish

Nitric Oxide Potentiation of Locomotor Activity in the Spinal Cord of the Lamprey

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