Low micromolar concentrations of 4-aminopyridine facilitate fictive locomotion expressed by the rat spinal cord in vitro

doi:10.1016/j.neuroscience.2004.03.045

Neuroscience

Volume 126, Issue 2, 2004, Pages 511-520

https://doi.org/10.1016/j.neuroscience.2004.03.045 Get rights and content

Abstract

Upregulating the operation of spinal locomotor networks is one mechanism to restore, at least partially, lesion-impaired locomotion. We investigated if the K⁺ channel blocker 4-aminopyridine (4-AP) could facilitate spinal locomotor networks in addition to its well-known effect on motor nerve conduction. Fictive locomotor patterns were recorded from ventral roots (VRs) of the isolated spinal cord of the neonatal rat. 4-AP (0.1–50 μM) produced synchronous VR oscillations which did not develop into fictive locomotion. These oscillations had network origin, required intact glutamatergic transmission and were probably amplified via electrotonic coupling because of their depression by the selective gap junction blocker carbenoxolone. 4-AP (5 μM) slightly increased input resistance of lumbar motoneurons without affecting their action or resting potentials. Dorsal root (DR) evoked synaptic responses were enhanced (217±65%) by 5 μM 4-AP without changes in axon conduction. 4-AP (5 μM) accelerated fictive locomotion induced by N-methyl-d-aspartate (NMDA) and serotonin (5-HT) without altering cycle amplitude and facilitated the onset of fictive locomotion in the presence of sub-threshold concentrations of NMDA and 5-HT. Furthermore, in the presence of 4-AP, weak DR stimuli, previously insufficient to activate locomotor patterns, generated alternating VR discharges. Thus, although 4-AP per se could not directly activate the locomotor network of the spinal cord, it could strongly facilitate the locomotor program initiated by neurochemicals or electrical stimuli. These data suggest that the reported improvement by 4-AP in locomotor activity of spinal-injury patients may include activation of locomotor networks when low concentrations of this drug are administered in coincidence with appropriate stimuli.

Section snippets

Experimental procedures

In accordance with NIH guidelines and the Italian act DL 27/1/92 n. 116 (implementing the European Community directives n. 86/609 and 93/88), experiments were performed on lumbar spinal cord preparations isolated from neonatal Wistar rats (0–5 days old) under urethane anesthesia (0.2 ml i.p. of a 10% w/v solution). All efforts were made to reduce the number of animals used and to minimize animal suffering. The experimental setup was the same as described by Marchetti et al. (2003), while full

Results

The database of the present study comprises 17 intracellularly recorded motoneurons with −77±5 mV resting potential and 37±13 MΩ input resistance. VR responses were collected from 71 spinal cord preparations.

Discussion

The principal finding of the present study is that low μM doses of 4-AP together with appropriate paradigms of concurrent CPG stimulation could activate and facilitate the function the locomotor CPG in the rat spinal cord. This result indicates that the mechanisms responsible for the action by 4-AP on spinal injury patients should include a central action of 4-AP, in addition to its well documented effect on conduction of nerve fibers (reviewed by Nashmi and Fehlings, 2001). In the absence of

Acknowledgements

This work was supported by a FIRB grant from MIUR.

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Low micromolar concentrations of 4-aminopyridine facilitate fictive locomotion expressed by the rat spinal cord in vitro

Abstract

Section snippets

Experimental procedures

Results

Discussion

Acknowledgements

Neurosci Lett

Brain Res

J Neurol Sci

Auton Neurosci

Brain Res Rev

Brain Res

Neuroscience

J Neurosci Methods

Brain Res

Brain Res

Brain Res

Prog Neurobiol

Trends Neurosci

Brain Res Bull

Neuroscience

Neuron

Neuroscience

Neuroscience

Brain Res

Brain Res

Depression of windup of spinal neurons in the neonatal rat spinal cord in vitro by an NK3 tachykinin receptor antagonist

J Neurophysiol

Interaction between disinhibited bursting and fictive locomotor patterns in the rat isolated spinal cord

J Neurophysiol

The effects of 4-aminopyridine and tetraethylammonium ions on normal and demyelinated mammalian nerve fibres

J Physiol

Spontaneous rhythmic bursts induced by pharmacological block of inhibition in lumbar motoneurons of the neonatal rat spinal cord

J Neurophysiol

Localization of rhythmogenic networks responsible for spontaneous bursts induced by strychnine and bicuculline in the rat isolated spinal cord

J Neurosci