Motor Alterations Induced by Chronic 4-Aminopyridine Infusion in the Spinal Cord In vivo: Role of Glutamate and GABA Receptors

Abstract

Motor neuron (MN) degeneration is the pathological hallmark of MN diseases, a group of neurodegenerative disorders clinically manifested as muscle fasciculations and hyperreflexia, followed by paralysis, respiratory failure, and death. Ample evidence supports a role of glutamate-mediated excitotoxicity in motor death. In previous work we showed that stimulation of glutamate release from nerve endings by perfusion of the K+-channel blocker 4-aminopyridine (4-AP) in the rat hippocampus induces seizures and neurodegeneration, and that AMPA infusion in the spinal cord produces paralysis and MN death. On these bases, in this work we have tested the effect of the chronic infusion of 4-AP in the spinal cord, using implanted osmotic minipumps, on motor activity and on MN survival, and the mechanisms underlying this effect. 4-AP produced muscle fasciculations and motor deficits assessed in two motor tests, which start 2–3 h after the implant, which ameliorated spontaneously within 6–7 days, but no neurodegeneration. These effects were prevented by both AMPA and NMDA receptors blockers. The role of GABAA receptors was also explored, and we found that chronic infusion of bicuculline induced moderate MN degeneration and enhanced the hyperexcitation produced by 4-AP. Unexpectedly, the GABAAR agonist muscimol also induced motor deficits and failed to prevent the MN death induced by AMPA. We conclude that motor alterations induced by chronic 4-AP infusion in the spinal cord in vivo is due to ionotropic glutamate receptor overactivation and that blockade of GABAergic neurotransmission induces MN death under chronic conditions. These results shed light on the role of glutamatergic and GABAergic neurotransmission in the regulation of MN excitability in the spinal cord.

Quercetin prevents spinal motor neuron degeneration induced by chronic excitotoxic stimulus by a sirtuin 1-dependent mechanism

“…Our group has previously reported that chronic infusion of AMPA into the rat spinal cord in vivo induces paralysis, MN degeneration and astrogliosis [ 12 , 24 ]. In these studies a 7.5 mM concentration was used and this caused a relatively rapid (~3 days) paralysis and MN death, which makes testing potential neuroprotective drugs difficult.…”

Transcranial Magnetic Stimulation as a Potential Biomarker in Multiple Sclerosis: A Systematic Review with Recommendations for Future Research

“…TMS findings in MS could also be related to changes in GABA-ergic or cholinergic signaling, both of which are disturbed throughout the disease [98, 100–102]; however, given much of this evidence is gleaned from animal models or indirect findings, this discussion is highly speculative. Disruption in GABA-ergic transmission accompanies glutamate-mediated excitotoxicity [101, 102] and may be related to motor features in MS [102]. In animal research, the administration of valproic acid and phenobarbitone, drugs acting on GABA A receptors, was found to improve clinical status and inhibits glutamate-mediated excitotoxicity [101].…”

Synaptic Transmission and Motoneuron Excitability Defects in Amyotrophic Lateral Sclerosis

“…Both acute and chronic infusion of bicuculline (a GABA A receptor blocker) generates a dose-dependent and temporary muscular hyperexcitability, motor deficits, and loss of motoneurons, showing that inhibitory GABAergic blockade can generate hyperexcitability of the intraspinal neuronal circuits and motoneuron degeneration (52). In addition, increased motoneuron loss and total paralysis was observed when 4-amynopyridine or a low dose of α-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid was added (52,53), suggesting a close functional link between glutamatergic transmission and GABAergic circuits in the regulation of motoneuron excitability. Considering that the use of strychnine (a glycine receptor blocker) has no significant effect and that glycinergic neurotransmission is mainly intersegmental (54), the GABAergic modulatory role appears to be intrasegmental, in line with evidence that ipsilateral flexor-extensor alternations are governed by GABAergic neurons directly affecting motoneuron activity within each spinal segment.…”