Chronic GABAergic blockade in the spinal cord in vivo induces motor alterations and neurodegeneration.
Inhibitory GABAergic and glycinergic neurotransmission in the spinal cord play a central role in the regulation of neuronal excitability, by maintaining a balance with the glutamate-mediated excitatory transmission. Glutamatergic agonists infusion in the spinal cord induce motor neuron death by excitotoxicity, leading to motor deficits and paralysis, but little is known on the effect of the blockade of inhibitory transmission. In this work we studied the effects of GABAergic and glycinergic blockade, by means of microdialysis perfusion (acute administration) and osmotic minipumps infusion (chronic administration) of GABA and glycine receptors antagonists directly in the lumbar spinal cord. We show that acute glycinergic blockade with strychnine or GABAergic blockade with bicuculline had no significant effects on motor activity and on motor neuron survival. However, chronic bicuculline infusion, but not strychnine, induced ipsilateral gait alterations, phalange flaccidity and significant motor neuron loss, and these effects were prevented by AMPA receptor blockade with CNQX but not by NMDA receptor blockade with MK801. In addition, we demonstrate that the chronic infusion of bicuculline enhanced the excitotoxic effect of AMPA, causing faster bilateral paralysis and increasing motor neuron loss. These findings indicate a relevant role of GABAergic inhibitory circuits in the regulation of motor neuron excitability and suggest that their alterations may be involved in the neurodegeneration processes characteristic of motor neuron diseases such as amyotrophic lateral sclerosis.
División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, 04510 Ciudad de México, Mexico.
Uri Nimrod
UN
Ramírez-Jarquín
División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, 04510 Ciudad de México, Mexico. Electronic address: rtapia@ifc.unam.mx.
Ricardo
R
Tapia
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D001284:Atrophy / Q000139:chemically induced; D001640:Bicuculline / Q000037:antagonists & inhibitors / Q000633:toxicity*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004347:Drug Interactions; D018756:GABA Antagonists / Q000633:toxicity*; D005684:Gait / Q000187:drug effects; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D009046:Motor Neurons / Q000187:drug effects*; D009123:Muscle Hypotonia / Q000139:chemically induced; D009410:Nerve Degeneration / Q000139:chemically induced*; D051381:Rats; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors; D013116:Spinal Cord / Q000187:drug effects*; D013331:Strychnine / Q000037:antagonists & inhibitors / Q000633:toxicity*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000633:toxicity
D018756:GABA Antagonists; D018009:Receptors, Glycine; D016291:Dizocilpine Maleate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D013331:Strychnine; D001640:Bicuculline
AMPA receptor; Excitotoxicity; GABA; Glycine; Motor neuron; Spinal cord