Differential modulation by monoamine membrane receptor agonists of reticulospinal input to lamina VIII feline spinal commissural interneurons

Hammar, Ingela; Stecina, Katinka; Jankowska, E.

doi:10.1111/j.1460-9568.2007.05764.x

Cited by 21 publications

(16 citation statements)

References 66 publications

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“…Relevant to our work, stimulation of the rostroventral medulla in rodents led to a facilitation of nociception at low stimulus intensities, while higher stimulus intensities were found to be inhibitory (Zhuo & Gebhart, 1997). Differential excitatory and inhibitory effects of 5‐HT has also been reported for the control of locomotion and modulation of mono‐ and polysynaptic reflexes (Beato & Nistri, 1998; Jankowska et al 2000; Schmidt & Jordan, 2000; Hammar et al 2002, 2007; Gordon & Whelan, 2006). Exogenously applied 5‐HT acts by way of postsynaptic 5‐HT 1A and 5‐HT 1B/D receptors to decrease the frequency of rhythmic activity (Beato & Nistri, 1998; Hochman et al 2001), while on the other hand activating 5‐HT 2 and 5‐HT 7 receptors to boost excitability (Beato & Nistri, 1998; Madriaga et al 2004; Liu & Jordan, 2005; Liu et al 2009).…”

Section: Discussionmentioning

confidence: 87%

Endogenous extracellular serotonin modulates the spinal locomotor network of the neonatal mouse

Dunbar

Tran

Whelan

2010

The Journal of Physiology

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Serotonin (5-HT) can potently activate and modulate spinal locomotor circuits in a variety of species. Many of these findings have been obtained by applying serotonin exogenously to the isolated spinal cord of in vitro preparations, which has the drawback of indiscriminately activating extrasynaptic receptors and neurons. To investigate the role of endogenously released serotonin in modulating locomotor networks, the selective serotonin reuptake inhibitor citalopram was used. Fictive locomotion was elicited by either electrical stimulation of the brainstem or the sacral 4 (S4) dorsal root. The addition of 20 μm of citalopram caudal to thoracic segment 5 (T5) had an overall inhibitory effect on the lumbar central pattern generator (CPG). Left-right and flexor-extensor coupling were significantly decreased, and there was also a phase shift in the flexor-extensor relationship. In addition, there was a significant decrease in burst amplitude. These effects were observed during both afferent and brainstem evoked fictive locomotion. When citalopram was added in the presence of 5-HT 1A and 5-HT 1B antagonists, the inhibitory effects were largely reversed. The remaining excitatory effects were mediated by 5-HT 7 and 5-HT 2 receptors. These results suggest that endogenous 5-HT release can modulate locomotor-like activity early in neonatal development.

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Section: Discussionmentioning

confidence: 87%

Endogenous extracellular serotonin modulates the spinal locomotor network of the neonatal mouse

Dunbar

Tran

Whelan

2010

The Journal of Physiology

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“…Furthermore, computer models of the CPG indicate that excitatory responses that start depressed but then augment during bursts, like reticulospinal and EIN responses in 5-HT, favor lower frequency output (Kozlov et al 2001). It is also striking that this effect is synergistic with the postsynaptic effects of 5-HT, which slow locomotion by acting at entirely different loci (Hounsgaard and Kiehn 1989; Wallen et al 1989; Zhong et al 2006; Hammar et al 2007). Clearly, while the presynaptic action of 5-HT is in one sense simple – Gβγ released in the presynaptic terminal directly targets the SNARE complex – it leads to complex synaptic and systemic outcomes.…”

Section: Discussionmentioning

confidence: 98%

Presynaptic G-Protein-Coupled Receptors Dynamically Modify Vesicle Fusion, Synaptic Cleft Glutamate Concentrations, and Motor Behavior

Gerachshenko¹,

Schwartz²,

Bleckert³

et al. 2009

J. Neurosci.

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Understanding how neuromodulators regulate behavior requires investigating their effects on functional neural systems, but also their underlying cellular mechanisms. Utilizing extensively characterized lamprey motor circuits, and the unique access to reticulospinal presynaptic terminals in the intact spinal cord that initiate these behaviors, we investigated effects of presynaptic G-protein-coupled receptors on locomotion from the systems level, to the molecular control of vesicle fusion. 5-HT inhibits neurotransmitter release via a G␤␥ interaction with the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex that promotes kissand-run vesicle fusion. In the lamprey spinal cord, we demonstrate that, although presynaptic 5-HT receptors inhibit evoked neurotransmitter release from reticulospinal command neurons, their activation does not abolish locomotion but rather modulates locomotor rhythms. Liberation of presynaptic G␤␥ causes substantial inhibition of AMPA receptor-mediated synaptic responses but leaves NMDA receptor-mediated components of neurotransmission mostly intact. Because G␤␥ binding to the SNARE complex is displaced by Ca 2ϩ -synaptotagmin binding, 5-HT-mediated inhibition displays Ca 2ϩ sensitivity. We show that, as Ca 2ϩ accumulates presynaptically during physiological bouts of activity, 5-HT/G␤␥-mediated presynaptic inhibition is relieved, leading to a frequency-dependent increase in synaptic concentrations of glutamate. This frequency-dependent phenomenon mirrors a shift in the vesicle fusion mode and a recovery of AMPA receptor-mediated EPSCs from inhibition without a modification of NMDA receptor EPSCs. We conclude that activation of presynaptic 5-HT G-protein-coupled receptors state-dependently alters vesicle fusion properties to shift the weight of NMDA versus AMPA receptor-mediated responses at excitatory synapses. We have therefore identified a novel mechanism in which modification of vesicle fusion modes may profoundly alter locomotor behavior.

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“…It is probable that noradrenergic inputs are important regulators of interlimb coordination in the intact state. Furthermore, commissural interneurons interposed in crossed reflex pathways are located in laminae VI–VIII in the cat (Edgley et al 2003; Hammar et al 2004, 2007; Jankowska et al 2009), regions that are densely packed with locomotor‐related α 2 ‐noradrenergic receptors (Noga et al 2011).…”

Section: Discussionmentioning

confidence: 99%

Differential modulation of crossed and uncrossed reflex pathways by clonidine in adult cats following complete spinal cord injury

Frigon

Johnson

Heckman

2012

The Journal of Physiology

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Non-technical summary Clonidine, a noradrenaline-like drug, facilitates the recovery of hindlimb walking in adult cats following a complete spinal cord injury.We show that clonidine improves operation of reflex pathways that coordinate bilateral hindlimb activity in cats after spinal cord injury. In addition, sensory signals from the periphery more easily activate the spinal network involved in producing locomotion following clonidine injection.These results show that spinal neurons that produce locomotion and coordinate bilateral activity become more excitable with clonidine.These data could help identify neurons of the spinal locomotor network and lead to a better pharmacotherapy in spinal cord-injured humans.Abstract Clonidine, an α-noradrenergic agonist, facilitates hindlimb locomotor recovery after complete spinal transection (i.e. spinalization) in adult cats. However, the mechanisms involved in clonidine-induced functional recovery are poorly understood. Sensory feedback from the legs is critical for hindlimb locomotor recovery in spinalized mammals and clonidine could alter how spinal neurons respond to peripheral inputs in adult spinalized cats. To test this hypothesis we evaluated the effect of clonidine on the responses of hindlimb muscles, primarily in the left hindlimb, evoked by stretching the left triceps surae muscles and by stimulating the right tibial and superficial peroneal nerves in eight adult decerebrate cats that were spinalized 1 month before the terminal experiment. Cats were not trained following spinalization. Clonidine had no consistent effect on responses of ipsilateral muscles evoked by triceps surae muscle stretch. However, clonidine consistently potentiated the amplitude and duration of crossed extensor responses. Moreover, following clonidine injection, stretch and tibial nerve stimulation triggered episodes of locomotor-like activity in approximately one-third of trials. Differential effects of clonidine on crossed reflexes and on ipsilateral responses to muscle stretch indicate an action at a pre-motoneuronal site. We conclude that clonidine facilitates hindlimb locomotor recovery following spinalization in untrained cats by enhancing the excitability of central pattern generating spinal neurons that also participate in crossed extensor reflex transmission.

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Differential modulation by monoamine membrane receptor agonists of reticulospinal input to lamina VIII feline spinal commissural interneurons

Cited by 21 publications

References 66 publications

Endogenous extracellular serotonin modulates the spinal locomotor network of the neonatal mouse

Endogenous extracellular serotonin modulates the spinal locomotor network of the neonatal mouse

Presynaptic G-Protein-Coupled Receptors Dynamically Modify Vesicle Fusion, Synaptic Cleft Glutamate Concentrations, and Motor Behavior

Differential modulation of crossed and uncrossed reflex pathways by clonidine in adult cats following complete spinal cord injury

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