The spinal GABA system modulates burst frequency and intersegmental coordination in the lamprey: differential effects of GABAA and GABAB receptors

1993 ◽  
Vol 69 (3) ◽  
pp. 647-657 ◽  
Author(s):  
J. Tegner ◽  
T. Matsushima ◽  
A. el Manira ◽  
S. Grillner
Keyword(s):  
Spinal Cord ◽  
Locomotor Activity ◽  
Gabaa Receptor ◽  
Gabab Receptor ◽  
Gaba Uptake ◽  
Phase Lag ◽  
Fictive Locomotion ◽  
Burst Frequency ◽  
Intersegmental Coordination ◽  
Burst Pattern

1. The effect of spinal GABAergic neurons on the segmental neuronal network generating locomotion has been analyzed in the lamprey spinal cord in vitro. It is shown that gamma-aminobutyric acid (GABA)A- and GABAB-mediated effects influence the burst frequency and the intersegmental coordination and that the GABA system is active during normal locomotor activity. 2. Fictive locomotor activity was induced by superfusing the spinal cord with a Ringer solution containing N-methyl-D-aspartate (NMDA, 150 microM). The efferent locomotor activity was recorded by suction electrodes from the ventral roots or intracellularly from interneurons or motoneurons. If a GABA uptake blocker was added to the perfusate, the burst rate decreased. This effect was counteracted by GABAB receptor blockade by phaclofen or 2-(OH)-saclofen. If instead a GABAB receptor agonist (baclofen) was added during fictive locomotion, a depression of the burst rate occurred. It was concluded that a GABAB receptor activation due to an endogenous release of GABA caused a depression of the burst activity with a maintained well-coordinated locomotor activity. 3. If a GABAA receptor antagonist (bicuculline) is applied during fictive locomotion elicited by NMDA, a certain increase of the burst rate occurred. Conversely, if a selective GABAA agonist (muscimol) was administered, the burst rate decreased. Similarly, if the GABAA receptor activity was potentiated by activation of a benzodiazepine site by diazepam, the burst rate was reduced. If, however the GABAergic effect was first enhanced by an uptake blocker (nipecotic acid), an administration of a GABAA antagonist (bicuculline) increased the burst rate, but in addition, the burst pattern became less regular with recurrent shorter periods without clear reciprocal burst activity. The GABAA receptor activity appears important for the rate control and for permitting a regular burst pattern. 4. The intersegmental coordination in the lamprey is characterized by a rostrocaudal constant phase lag of approximately 1% of the cycle duration between the activation of consecutive segments during forward swimming. This rostrocaudal phase lag can be reversed during backward swimming, which can be induced also experimentally in the isolated spinal cord by providing a higher excitability to the caudal segments. In a split-bath configuration, a GABA uptake blocker or a GABAB agonist was administered to the rostral part of the spinal cord, which caused a reversal of the phase lag as during backward swimming. If GABAA receptors were blocked under similar conditions, the intersegmental coordination became irregular. It is concluded that an increased GABA activity in a spinal cord region can modify the intersegmental coordination.(ABSTRACT TRUNCATED AT 400 WORDS)

Endogenous Tachykinin Release Contributes to the Locomotor Activity in Lamprey

2007 ◽  
Vol 97 (5) ◽  
pp. 3331-3339 ◽  
Author(s):  
Carolina Thörn Pérez ◽  
Russell H. Hill ◽  
Sten Grillner
Keyword(s):  
Spinal Cord ◽  
Steady State ◽  
Locomotor Activity ◽  
Initial Period ◽  
Burst Frequency ◽  
Ongoing Activity ◽  
Initial Burst ◽  
Tachykinin Receptor ◽  
Spinal Network ◽  
Endogenous Release

Tachykinins are present in lamprey spinal cord. The goal of this study was to investigate whether an endogenous release of tachykinins contributes to the activity of the spinal network generating locomotor activity. The locomotor network of the isolated lamprey spinal cord was activated by bath-applied N-methyl-d-aspartate (NMDA) and the efferent activity recorded from the ventral roots. When spantide II, a tachykinin receptor antagonist, was bath-applied after reaching a steady-state burst frequency (>2 h), it significantly lowered the burst rate compared with control pieces from the same animal. In addition, the time to reach the steady-state burst frequency (>2 h) was lengthened in spantide II. These data indicate that an endogenous tachykinin release contributes to the ongoing activity of the locomotor network by modulating the glutamate–glycine neuronal network responsible for the locomotor pattern. We also explored the effects of a 10-min exogenous application of substance P (1 μM), a tachykinin, and showed that its effect on the burst rate depended on the initial NMDA induced burst frequency. At low initial burst rates (∼0.5 Hz), tachykinins caused a marked further slowing to 0.1 Hz, whereas at higher initial burst rates, it instead caused an enhanced burst rate as previously reported, and in addition, a slower modulation (0.1 Hz) of the amplitude of the motor activity. These effects occurred during an initial period of ∼1 h, whereas a modest long-lasting increase of the burst rate remained after >2 h.

Local serotonergic modulation of calcium-dependent potassium channels controls intersegmental coordination in the lamprey spinal cord

1992 ◽  
Vol 67 (6) ◽  
pp. 1683-1690 ◽  
Author(s):  
T. Matsushima ◽  
S. Grillner
Keyword(s):  
Spinal Cord ◽  
Time Lag ◽  
Cycle Duration ◽  
Phase Lag ◽  
Intersegmental Coordination ◽  
Calcium Dependent ◽  
Bath Application ◽  
Serotonin System ◽  
5 Ht Uptake

1. The intersegmental coordination during undulatory locomotion in lamprey is characterized by a constant phase lag between consecutive segments, that is, the ratio between the intersegmental time lag and the cycle duration remains constant. It is shown that the spinal 5-HT (serotonin) system can, in a graded fashion, control the phase lag value from a rostrocaudal to a caudorostral lag corresponding to a reversed direction of swimming. These effects can be explained by a 5-HT-induced depression of Ca(2+)-dependent K+ channels (KCa channels) in network neurons. 2. The actions of the spinal 5-HT system were analyzed in the lamprey spinal cord preparation in vitro. Fictive swimming was induced by bath application of N-methyl-D-aspartate (NMDA). The intersegmental phase lag between ventral root burst activities was measured along the ipsilateral side of the spinal cord. The chamber with the preparation was partitioned into two pools so that the rostral and caudal halves of the preparation could be perfused independently with solutions containing the same level of NMDA (100-150 microM) with or without additional 5-HT or a 5-HT uptake blocker (citalopram). 3. Addition of 5-HT to one of these partitioned pools changed the intersegmental phase lag in this pool, whereas the cycle duration remained unchanged. It was determined by the activity in the "non-5-HT" pool. Addition of 5-HT to the caudal pool resulted in an increased rostrocaudal phase lag. When 5-HT was added to the rostral pool, on the other hand, the phase lag shifted direction to a backward coordination.(ABSTRACT TRUNCATED AT 250 WORDS)

Synaptic transmission between ventrolateral funiculus axons and lumbar motoneurons in the isolated spinal cord of the neonatal rat

1994 ◽  
Vol 72 (5) ◽  
pp. 2406-2419 ◽  
Author(s):  
M. Pinco ◽  
A. Lev-Tov
Keyword(s):  
Spinal Cord ◽  
Nmda Receptor ◽  
Gabaa Receptor ◽  
Gabab Receptor ◽  
Short Latency ◽  
Neonatal Rat ◽  
Gamma Aminobutyric Acid ◽  
Long Latency ◽  
Ventrolateral Funiculus

1. We studied the projections of ventrolateral funiculus (VLF) axons to lumbar motoneurons in the in vitro spinal cord preparation of 1- to 6-day-old rats using extracellular and sharp-electrode intracellular recordings. 2. Ipsilateral and contralateral VLF projections to lumbar motoneurons (L4-L5) could be activated in the neonatal rat by stimulation of the surgically peeled VLF at the rostral (L1-L2) and caudal lumbar (L6) cord. Motoneurons were activated ipsilaterally through short- and long-latency projections in all cases and contralaterally through long-latency projections in most cases. 3. Suppression of the excitatory components of VLF postsynaptic potentials (PSPs) by application of the specific antagonists of N-methyl D-aspartate (NMDA) and non-NMDA receptors, 2-amino-5-phosphonovaleric acid (APV) and 6-cyano-7-nitroquin-oxaline-2,3-dione (CNQX), revealed depolarizing PSPs that could be reversed at -55 to -60 mV by injection of depolarizing current steps to the motoneurons. These depolarizing PSPs were blocked by addition of strychnine and bicuculline and are therefore suggested to be glycine and gamma-aminobutyric acid-A (GABAA) receptor-mediated inhibitory PSPs. The identity of a small (< or = 0.2 mV) residual depolarizing component that persisted in the presence of APV, CNQX, strychnine, and bicuculline remains to be determined. 4. Short-latency excitatory PSPs (EPSPs) could be resolved from the ipsilaterally elicited VLF PSPs after the reduction of the polysynaptic activity in the preparation by administration of mephenesin, which was followed by suppression of the glycine and GABAA receptor-mediated components of the PSPs by bath application of strychnine and bicuculline. The latencies of these EPSPs were similar to those of the monosynaptic dorsal root afferent EPSPs recorded from the same motoneurons. These short-latency VLF EPSPs were shortened by the NMDA antagonist APV and revealed an NMDA receptor-mediated component after administration of the non-NMDA receptor antagonist CNQX. Addition of the GABAB receptor agonist L-(-) baclofen or the glutamate analogue L-2-amino-4-phosphonobutyric acid (L-AP4) attenuated the pharmacologically resolved short-latency EPSPs.(ABSTRACT TRUNCATED AT 400 WORDS)

The Spinal GABAergic System Is a Strong Modulator of Burst Frequency in the Lamprey Locomotor Network

2004 ◽  
Vol 92 (4) ◽  
pp. 2357-2367 ◽  
Author(s):  
David E. Schmitt ◽  
Russell H. Hill ◽  
Sten Grillner
Keyword(s):  
Spinal Cord ◽  
Detailed Analysis ◽  
Gabaergic Neurons ◽  
Ventral Root ◽  
Gabaergic System ◽  
Frequency Regulation ◽  
Fictive Locomotion ◽  
Burst Frequency ◽  
Pronounced Increase ◽  
Spinal Network

The spinal network coordinating locomotion is comprised of a core of glutamate and glycine interneurons. This network is modulated by several transmitter systems including spinal GABA interneurons. The purpose of this study is to explore the contribution of GABAergic neurons to the regulation of locomotor burst frequency in the lamprey model. Using gabazine, a competitive GABAA antagonist more specific than bicuculline, the goal was to provide a detailed analysis of the influence of an endogenous activation of GABAA receptors on fictive locomotion, as well as their possible interaction with GABAB and involvement of GABAC receptors. During N-methyl-d-aspartate (NMDA)-induced fictive locomotion (ventral root recordings in the isolated spinal cord), gabazine (0.1–100 μM) significantly increased the burst rate up to twofold, without changes in regularity or “burst quality.” Gabazine had a proportionately greater effect at higher initial burst rates. Picrotoxin (1–7.5 μM), a less selective GABAA antagonist, also produced a pronounced increase in frequency, but at higher concentrations, the rhythm deteriorated, likely due to the unspecific effects on glycine receptors. The selective GABAB antagonist CGP55845 also increased the frequency, and this effect was markedly enhanced when combined with the GABAA antagonist gabazine. The GABAC antagonist (1,2,5,6-tetrahydropyridine-4-yl)methylphosphinic acid (TPMPA) had no effect on locomotor bursting. Thus the spinal GABA system does play a prominent role in burst frequency regulation in that it reduces the burst frequency by ≤50%, presumably due to presynaptic and soma-dendritic effects documented previously. It is not required for burst generation, but acts as a powerful modulator.

scholarly journals Fast and Slow Locomotor Burst Generation in the Hemispinal Cord of the Lamprey

2003 ◽  
Vol 89 (6) ◽  
pp. 2931-2942 ◽  
Author(s):  
Lorenzo Cangiano ◽  
Sten Grillner
Keyword(s):  
Spinal Cord ◽  
Reciprocal Inhibition ◽  
Pattern Generation ◽  
Burst Activity ◽  
Burst Frequency ◽  
Glutamatergic Neurons ◽  
Voltage Dependent ◽  
Burst Pattern ◽  
Glycinergic Inhibition ◽  
Electrical Stimuli

A fundamental question in vertebrate locomotion is whether distinct spinal networks exist that are capable of generating rhythmic output for each group of muscle synergists. In many vertebrates including the lamprey, it has been claimed that burst activity depends on reciprocal inhibition between antagonists. This question was addressed in the isolated lamprey spinal cord in which the left and right sides of each myotome display rhythmic alternating activity. We sectioned the spinal cord along the midline and tested whether rhythmic motor activity could be induced in the hemicord with bath-applied d-glutamate or N-methyl-d-aspartate (NMDA) as in the intact spinal cord or by brief trains of electrical stimuli. Fast rhythmic bursting (2–12 Hz), coordinated across ventral roots, was observed with all three methods. Furthermore, to diminish gradually the crossed glycinergic inhibition, a progressive surgical lesioning of axons crossing the midline was implemented. This resulted in a gradual increase in burst frequency, linking firmly the fast hemicord rhythm [6.6 ± 1.7 (SD) Hz] to fictive swimming in the intact cord (2.4 ± 0.7 Hz). Ipsilateral glycinergic inhibition was not required for the hemicord burst pattern generation, suggesting that an interaction between excitatory glutamatergic neurons suffices to produce the unilateral burst pattern. In NMDA, burst activity at a much lower rate (0.1–0.4 Hz) was also encountered, which required the voltage-dependent properties of NMDA receptors in contrast to the fast rhythm. Swimming is thus produced by pairs of unilateral burst generating networks with reciprocal inhibitory connections that not only ensure left/right alternation but also downregulate frequency.

Extent and Role of Multisegmental Coupling in the Lamprey Spinal Locomotor Pattern Generator

2000 ◽  
Vol 83 (1) ◽  
pp. 465-476 ◽  
Author(s):  
William L. Miller ◽  
Karen A. Sigvardt
Keyword(s):  
Spinal Cord ◽  
Pattern Generator ◽  
Synaptic Activity ◽  
System Level ◽  
Oscillatory Activity ◽  
Stable Phase ◽  
Phase Lag ◽  
Intersegmental Coordination ◽  
Cycle Frequency ◽  
Phase Lags

Timing of oscillatory activity along the longitudinal body axis is critical for locomotion in the lamprey and other elongated animals. In the lamprey spinal locomotor central pattern generator (CPG), intersegmental coordination is thought to arise from the pattern of extensive connections made by propriospinal interneurons. However, the mechanisms responsible for intersegmental coordination remain unknown, in large part because of the difficulty in obtaining quantitative information on these multisegmental fibers. System-level experiments were performed on isolated 50-segment preparations of spinal cord of adult silver lampreys, Ichthyomyzon unicuspis, to determine the dependence of CPG performance on multisegmental coupling. Coupling was manipulated through use of an experiment chamber with movable partitions, which allowed separate application of solution to rostral, middle, and caudal regions of the spinal cord preparation. During control trials, fictive locomotion, induced by bath application ofd-glutamate in all three regions, was recorded extracellularly from ventral roots. Local synaptic activity in a variable number of middle segments was subsequently blocked with a low-Ca2+, high-Mn2+ saline solution in the middle compartment, whereas conduction in axons spanning the middle segments was unaffected. Spectral analysis was used to assess the effects of blocking propriospinal coupling on intersegmental phase lag, rhythm frequency, correlation, and variability. Significant correlation and a stable phase lag between the rostral and caudal regions of the spinal cord preparation were maintained during block of as many as 16 and sometimes 20 intervening segments. However, the mean value of this rostrocaudal phase decreased with increasing number of blocked segments from the control value of approximately 1% per segment. By contrast, phase lags within the rostral and caudal end regions remained unaffected. The cycle frequency in the rostral and caudal regions decreased with the number of blocked middle segments and tended to diverge when a large number of middle segments was blocked. The variability in cycle frequency and intersegmental phase both increased with increasing number of blocked segments. In addition, a number of differences were noted in the properties of the motor output of the rostral and caudal regions of the spinal cord. The results indicate that the maximal functional length of propriospinal coupling fibers is at least 16–20 segments in I. unicuspis, whereas intersegmental phase lags are controlled at a local level and are not dependent on extended multisegmental coupling. Other possible roles for multisegmental coupling are discussed.

Intersegmental coordination of the leech swimming rhythm. II. Comparison of long and short chains of ganglia

1985 ◽  
Vol 54 (6) ◽  
pp. 1460-1472 ◽  
Author(s):  
R. A. Pearce ◽  
W. O. Friesen
Keyword(s):  
Chain Length ◽  
Nerve Cord ◽  
Conduction Block ◽  
Experimental Models ◽  
Cycle Period ◽  
Phase Lag ◽  
Intersegmental Coordination ◽  
Burst Pattern ◽  
Phase Lags ◽  
The Relationship

Preparations of the nearly isolated leech nerve cord containing as few as two ganglia are sufficient to generate intersegmentally coordinated swim oscillations, provided that they receive tonic excitation from other segments via the median connective (Faivre's nerve). Due to their greatly reduced complexity, these preparations should provide useful experimental models of neuronal coordination. As a step in the development of such models, we have characterized the intersegmental coordination of nerve-cord chains ranging from 2 to 18 ganglia in length. We found that increases in swim-cycle period give rise to increases in intersegmental delay between homologous motoneuron bursts. Thus the intersegmental phase relationships are nearly independent of period. The relationship between intersegmental delay and period is approximately linear and extrapolates to intersect the period axis at approximately 0.3 s. This value is in close agreement with the analogous measure derived from tension measurements in the intact swimming leech. Chain length (number of connected ganglia in a preparation) has a pronounced influence on the magnitude of intersegmental phase lag. The longest chains (18 ganglia) exhibited phase lags of approximately 8 degrees per segment, whereas for pairs of ganglia the phase lag was approximately 40 degrees per segment. This dependence of phase lags on chain length was apparent at both the motor and oscillator levels. The intersegmental phase lag is not the same in all parts of the nerve cord. Rather, it increases steadily toward the posterior end of the chain, providing a deceleration in the rearward progression of the metachronal activity. The rearward increase in intersegmental phase lag is paralleled by a propensity of chains taken from more posterior sections of the nerve cord to exhibit larger phase lags. That is, there appears to be a phase-lag gradient intrinsic to the nerve cord to account for the deceleration of activity. The anterior and posterior ends of an isolated nerve cord continue to exhibit phase-locked bursting when an intervening section of five ganglia is bathed in elevated Mg2+ saline. Thus, information sufficient to coordinate oscillations in separate ganglia travels at least six segments. The phase lag across the blocked section is reduced but within each unblocked section is increased so that the phase lag between extreme ends is nearly unchanged. This altered burst pattern is due to a combination of synaptic block in segmental ganglia and conduction block in through-fibers.

Modulation of calcium currents and membrane properties by substance P in the lamprey spinal cord

2013 ◽  
Vol 110 (2) ◽  
pp. 286-296 ◽  
Author(s):  
Carolina Thörn Pérez ◽  
Russell H. Hill ◽  
Sten Grillner
Keyword(s):  
Spinal Cord ◽  
Substance P ◽  
Calcium Channels ◽  
Calcium Channel ◽  
Input Resistance ◽  
Reciprocal Inhibition ◽  
Calcium Currents ◽  
Membrane Properties ◽  
Fictive Locomotion ◽  
Burst Frequency

Substance P is endogenously released within the locomotor network of the adult lamprey, accelerates the burst frequency of fictive locomotion, and reduces the reciprocal inhibition. Previous studies have shown that dopamine, serotonin, and GABA regulate calcium channels, which control neurotransmitter release, action potential duration, and slow afterhyperpolarization (sAHP). Here we examine the effect of substance P on calcium channels in motoneurons and commissural interneurons using whole cell patch clamp in the lamprey spinal cord. This study analyzed the effects of substance P on calcium currents activated in voltage clamp. We examined the calcium-dependent sAHP in current clamp, to determine the involvement of three calcium channel subtypes modulated by substance P. The effects of substance P on membrane potential and during N-methyl-d-aspartic acid (NMDA) induced oscillations were also analyzed. Depolarizing voltage steps induced inward calcium currents. Substance P reduced the currents carried by calcium by 61% in commissural interneurons and by 31% in motoneurons. Using specific calcium channel antagonists, we show that substance P reduces the sAHP primarily by inhibiting N-type (CaV2.2) channels. Substance P depolarized both motoneurons and commissural interneurons, and we present evidence that this occurs due to an increased input resistance. We also explored the effects of substance P on NMDA-induced oscillations in tetrodotoxin and found it caused a frequency increase. Thus the reduction of calcium entry by substance P and the accompanying decrease of the sAHP amplitude, combined with substance P potentiation of currents activated by NMDA, may both contribute to the increase in fictive locomotion frequency.

scholarly journals Rostrocaudal Distribution of the C-Fos-Immunopositive Spinal Network Defined by Muscle Activity during Locomotion

2021 ◽  
Vol 11 (1) ◽  
pp. 69
Author(s):  
Natalia Merkulyeva ◽  
Vsevolod Lyakhovetskii ◽  
Aleksandr Veshchitskii ◽  
Oleg Gorskii ◽  
Pavel Musienko
Keyword(s):  
Spinal Cord ◽  
Locomotor Activity ◽  
Control Systems ◽  
Muscle Activity ◽  
Knee Extensors ◽  
Emg Activity ◽  
Lumbosacral Spinal Cord ◽  
Adductor Muscles ◽  
Spinal Network ◽  
Hip Flexor

The optimization of multisystem neurorehabilitation protocols including electrical spinal cord stimulation and multi-directional tasks training require understanding of underlying circuits mechanisms and distribution of the neuronal network over the spinal cord. In this study we compared the locomotor activity during forward and backward stepping in eighteen adult decerebrated cats. Interneuronal spinal networks responsible for forward and backward stepping were visualized using the C-Fos technique. A bi-modal rostrocaudal distribution of C-Fos-immunopositive neurons over the lumbosacral spinal cord (peaks in the L4/L5 and L6/S1 segments) was revealed. These patterns were compared with motoneuronal pools using Vanderhorst and Holstege scheme; the location of the first peak was correspondent to the motoneurons of the hip flexors and knee extensors, an inter-peak drop was presumably attributed to the motoneurons controlling the adductor muscles. Both were better expressed in cats stepping forward and in parallel, electromyographic (EMG) activity of the hip flexor and knee extensors was higher, while EMG activity of the adductor was lower, during this locomotor mode. On the basis of the present data, which showed greater activity of the adductor muscles and the attributed interneuronal spinal network during backward stepping and according with data about greater demands on postural control systems during backward locomotion, we suppose that the locomotor networks for movements in opposite directions are at least partially different.

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

2018 ◽  
Vol 120 (3) ◽  
pp. 998-1009 ◽  
Author(s):  
David Acton ◽  
Matthew J. Broadhead ◽  
Gareth B. Miles
Keyword(s):  
Spinal Cord ◽  
Protein Kinase ◽  
Dopamine Receptor ◽  
Kinase Inhibitor ◽  
Ventral Horn ◽  
Skf 38393 ◽  
Network Activity ◽  
Related Activity ◽  
Burst Frequency ◽  
Spinal Motor

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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