scholarly journals Balanced cholinergic modulation of spinal locomotor circuits via M2 and M3 muscarinic receptors

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Filipe Nascimento ◽  
Lennart R. B. Spindler ◽  
Gareth B. Miles
Keyword(s):  
Spinal Cord ◽  
Outward Current ◽  
Receptor Activation ◽  
Receptor Blockade ◽  
Cellular Mechanisms ◽  
Synaptic Inputs ◽  
Motor Circuits ◽  
Spinal Motor ◽  
M3 Receptors ◽  
M3 Receptor

Abstract Neuromodulation ensures that neural circuits produce output that is flexible whilst remaining within an optimal operational range. The neuromodulator acetylcholine is released during locomotion to regulate spinal motor circuits. However, the range of receptors and downstream mechanisms by which acetylcholine acts have yet to be fully elucidated. We therefore investigated metabotropic acetylcholine receptor-mediated modulation by using isolated spinal cord preparations from neonatal mice in which locomotor-related output can be induced pharmacologically. We report that M2 receptor blockade decreases the frequency and amplitude of locomotor-related activity, whilst reducing its variability. In contrast, M3 receptor blockade destabilizes locomotor-related bursting. Motoneuron recordings from spinal cord slices revealed that activation of M2 receptors induces an outward current, decreases rheobase, reduces the medium afterhyperpolarization, shortens spike duration and decreases synaptic inputs. In contrast, M3 receptor activation elicits an inward current, increases rheobase, extends action potential duration and increases synaptic inputs. Analysis of miniature postsynaptic currents support that M2 and M3 receptors modulate synaptic transmission via different mechanisms. In summary, we demonstrate that M2 and M3 receptors have opposing modulatory actions on locomotor circuit output, likely reflecting contrasting cellular mechanisms of action. Thus, intraspinal cholinergic systems mediate balanced, multimodal control of spinal motor output.

scholarly journals The Involvement of CaV1.3 Channels in Prolonged Root Reflexes and Its Potential as a Therapeutic Target in Spinal Cord Injury

2021 ◽  
Vol 15 ◽  
Author(s):  
Mingchen C. Jiang ◽  
Derin V. Birch ◽  
Charles J. Heckman ◽  
Vicki M. Tysseling
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Motor System ◽  
Involuntary Movement ◽  
Intracellular Recordings ◽  
Plateau Potentials ◽  
Cellular Mechanisms ◽  
Spinal Motor ◽  
Cord Injury

Spinal cord injury (SCI) results in not only the loss of voluntary muscle control, but also in the presence of involuntary movement or spasms. These spasms post-SCI involve hyperexcitability in the spinal motor system. Hyperactive motor commands post SCI result from enhanced excitatory postsynaptic potentials (EPSPs) and persistent inward currents in voltage-gated L-type calcium channels (LTCCs), which are reflected in evoked root reflexes with different timings. To further understand the contributions of these cellular mechanisms and to explore the involvement of LTCC subtypes in SCI-induced hyperexcitability, we measured root reflexes with ventral root recordings and motoneuron activities with intracellular recordings in an in vitro preparation using a mouse model of chronic SCI (cSCI). Specifically, we explored the effects of 1-(3-chlorophenethyl)-3-cyclopentylpyrimidine-2,4,6-(1H,3H,5H)-trione (CPT), a selective negative allosteric modulator of CaV1.3 LTCCs. Our results suggest a hyperexcitability in the spinal motor system in these SCI mice. Bath application of CPT displayed slow onset but dose-dependent inhibition of the root reflexes with the strongest effect on LLRs. However, the inhibitory effect of CPT is less potent in cSCI mice than in acute SCI (aSCI) mice, suggesting changes either in composition of CaV1.3 or other cellular mechanisms in cSCI mice. For intracellular recordings, the intrinsic plateau potentials, was observed in more motoneurons in cSCI mice than in aSCI mice. CPT inhibited the plateau potentials and reduced motoneuron firings evoked by intracellular current injection. These results suggest that the LLR is an important target and that CPT has potential in the therapy of SCI-induced muscle spasms.

scholarly journals Adenosine-mediated modulation of ventral horn interneurons and spinal motoneurons in neonatal mice

2015 ◽  
Vol 114 (4) ◽  
pp. 2305-2315 ◽  
Author(s):  
Emily C. Witts ◽  
Filipe Nascimento ◽  
Gareth B. Miles
Keyword(s):  
Spinal Cord ◽  
Purinergic Signaling ◽  
Presynaptic Receptors ◽  
Ventral Horn ◽  
Cellular Mechanisms ◽  
Mouse Spinal Cord ◽  
Synaptic Inputs ◽  
Adenosine Receptor Antagonist ◽  
Postsynaptic Currents

Neuromodulation allows neural networks to adapt to varying environmental and biomechanical demands. Purinergic signaling is known to be an important modulatory system in many parts of the CNS, including motor control circuitry. We have recently shown that adenosine modulates the output of mammalian spinal locomotor control circuitry (Witts EC, Panetta KM, Miles GB. J Neurophysiol 107: 1925–1934, 2012). Here we investigated the cellular mechanisms underlying this adenosine-mediated modulation. Whole cell patch-clamp recordings were performed on ventral horn interneurons and motoneurons within in vitro mouse spinal cord slice preparations. We found that adenosine hyperpolarized interneurons and reduced the frequency and amplitude of synaptic inputs to interneurons. Both effects were blocked by the A1-type adenosine receptor antagonist DPCPX. Analysis of miniature postsynaptic currents recorded from interneurons revealed that adenosine reduced their frequency but not amplitude, suggesting that adenosine acts on presynaptic receptors to modulate synaptic transmission. In contrast to interneurons, recordings from motoneurons revealed an adenosine-mediated depolarization. The frequency and amplitude of synaptic inputs to motoneurons were again reduced by adenosine, but we saw no effect on miniature postsynaptic currents. Again these effects on motoneurons were blocked by DPCPX. Taken together, these results demonstrate differential effects of adenosine, acting via A1 receptors, in the mouse spinal cord. Adenosine has a general inhibitory action on ventral horn interneurons while potentially maintaining motoneuron excitability. This may allow for adaptation of the locomotor pattern generated by interneuronal networks while helping to ensure the maintenance of overall motor output.

VR1 Receptor Activation Induces Glutamate Release and Postsynaptic Firing in the Paraventricular Nucleus

2004 ◽  
Vol 92 (3) ◽  
pp. 1807-1816 ◽  
Author(s):  
De-Pei Li ◽  
Shao-Rui Chen ◽  
Hui-Lin Pan
Keyword(s):  
Spinal Cord ◽  
Paraventricular Nucleus ◽  
Glutamate Release ◽  
Receptor Activation ◽  
Ruthenium Red ◽  
Thoracic Spinal Cord ◽  
Synaptic Inputs ◽  
Postsynaptic Currents ◽  
Thoracic Spinal ◽  
Immunofluorescence Labeling

Neurons in the paraventricular nucleus (PVN) are important in regulating autonomic function through projections to the brain stem and spinal cord. Although the vanilloid receptors (VR1) are present in the PVN, their physiological function is scarcely known. In this study, we determined the role of VR1 receptors in the regulation of synaptic inputs and the excitability of spinally projecting PVN neurons. Whole cell patch-clamp recordings were performed on the PVN neurons labeled by a retrograde fluorescence tracer injected into the thoracic spinal cord of rats. Capsaicin significantly increased the frequency of glutamatergic miniature excitatory postsynaptic currents (mEPSCs) without changing the amplitude and decay time constant of mEPSCs. On the other hand, capsaicin had no effect on GABAergic miniature inhibitory postsynaptic currents (mIPSCs). The effect of capsaicin on mEPSCs was abolished by a specific VR1 antagonist, iodo-resiniferatoxin (iodo-RTX), or ruthenium red. Importantly, iodo-RTX per se significantly reduced the amplitude of evoked EPSCs and the frequency of mEPSCs. Removal of extracellular Ca2+, but not Cd2+ treatment, also eliminated the effect of capsaicin on mEPSCs. Furthermore, capsaicin caused a large increase in the firing rate of PVN neurons, and such an effect was abolished in the presence of ionotropic glutamate receptor antagonists. Additionally, the double-immunofluorescence labeling revealed that all of the VR1 immunoreactivity was colocalized with a presynaptic marker, synaptophysin, in the PVN. Thus this study provides the first evidence that activation of VR1 receptors excites preautonomic PVN neurons through selective potentiation of glutamatergic synaptic inputs. Presynaptic VR1 receptors and endogenous capsaicin-like substances in the PVN may represent a previously unidentified mechanism in hypothalamic regulation of the autonomic nervous system.

Rostrocaudal Progression in the Development of Periodic Spontaneous Activity in Fetal Rat Spinal Motor Circuits In Vitro

1999 ◽  
Vol 81 (5) ◽  
pp. 2592-2595 ◽  
Author(s):  
Kiyomi Nakayama ◽  
Hiroshi Nishimaru ◽  
Makito Iizuka ◽  
Shigeru Ozaki ◽  
Norio Kudo
Keyword(s):  
Spinal Cord ◽  
Receptor Antagonist ◽  
Spontaneous Activity ◽  
Cervical Region ◽  
Lumbar Region ◽  
Motor Circuits ◽  
Spinal Motor ◽  
Fetal Rat ◽  
Spontaneous Bursts

Rostrocaudal progression in the development of periodic spontaneous activity in fetal rat spinal motor circuits in vitro. Developmental changes in the periodic spontaneous bursts in cervical and lumbar ventral roots (VRs) were investigated using isolated spinal cord preparations obtained from rat fetuses at embryonic days ( E) 13.5–18.5. Spontaneous bursts were observed in the cervical VR at E13.5–17.5, and in the lumbar VR at E14.5–17.5. Bursts occurrence in the cervical and lumbar VRs was correlated in a 1:1 fashion at E14.5–16.5. The bursts in the cervical VR preceded those in the lumbar VR at E14.5, but the latter came to precede the former by E16.5. The interval between spontaneous bursts in the lumbar VR was greatly prolonged after spinal cord transection at the midthoracic level at E14.5, whereas that in the cervical VR became significantly longer at E14.5–16.5. These results suggest that the dominant neuronal circuit initiating the spontaneous bursts shifts from cervical to lumbar region during this period. Bath application of a glutamate receptor antagonist, kynurenate (4 mM), had little effect on the spontaneous bursts in either cervical or lumbar VRs at E14.5–15.5. At E16.5, kynurenate abolished the spontaneous bursts in the cervical VR. Concomitant application of kynurenate and strychnine (5 μM), a glycine receptor antagonist, abolished all spontaneous bursts, suggesting that the major transmitter mediating the spontaneous bursts changes from glycine to glutamate in the cervical region by E16.5, but not in the lumbar region during this period.

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.

scholarly journals Transient Activity Induces a Long-Lasting Increase in the Excitability of Olfactory Bulb Interneurons

2008 ◽  
Vol 99 (1) ◽  
pp. 187-199 ◽  
Author(s):  
Tsuyoshi Inoue ◽  
Ben W. Strowbridge
Keyword(s):  
Olfactory Bulb ◽  
Granule Cells ◽  
Receptor Activation ◽  
Brain Regions ◽  
Persistent Activity ◽  
Cellular Mechanisms ◽  
Calcium Dependent ◽  
Transient Activity ◽  
Olfactory Bulb Slices ◽  
Processing And Storage

Little is known about the cellular mechanisms that underlie the processing and storage of sensory in the mammalian olfactory system. Here we show that persistent spiking, an activity pattern associated with working memory in other brain regions, can be evoked in the olfactory bulb by stimuli that mimic physiological patterns of synaptic input. We find that brief discharges trigger persistent activity in individual interneurons that receive slow, subthreshold oscillatory input in acute rat olfactory bulb slices. A 2- to 5-Hz oscillatory input, which resembles the synaptic drive that the olfactory bulb receives during sniffing, is required to maintain persistent firing. Persistent activity depends on muscarinic receptor activation and results from interactions between calcium-dependent afterdepolarizations and low-threshold Ca spikes in granule cells. Computer simulations suggest that intrinsically generated persistent activity in granule cells can evoke correlated spiking in reciprocally connected mitral cells. The interaction between the intrinsic currents present in reciprocally connected olfactory bulb neurons constitutes a novel mechanism for synchronized firing in subpopulations of neurons during olfactory processing.

scholarly journals Early adenosine receptor activation ameliorates spinal cord reperfusion injury

2008 ◽  
Vol 9 (4) ◽  
pp. 363-367 ◽  
Author(s):  
T Brett Reece ◽  
Curtis G Tribble ◽  
David O Okonkwo ◽  
Jonathon D Davis ◽  
Thomas S Maxey ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Reperfusion Injury ◽  
Adenosine Receptor ◽  
Receptor Activation ◽  
Adenosine Receptor Activation
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