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Media type:
E-Book
Title:
Spontaneous Neurogenic Electromyographic Activities in ALS G93A Rats, Potential Over-Excitatory Drive Leading to Alpha Motor Neuron Degeneration
Published:
[Erscheinungsort nicht ermittelbar]: eScholarship, University of California, 2018
Language:
English
Origination:
University thesis:
Dissertation, eScholarship, University of California, 2018
Footnote:
Description:
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by a progressive degeneration of alpha-motor neurons, which results in motor-ambulatory and respiratory dysfunction. One of the proposed mechanisms generally believed to play a critical role in initiating alpha-motor neuron degeneration, is the hyperexcitable drive mediated by glutamatergic receptors in excitatory synapses due to elevated synaptic glutamates. However, no direct elctrophysiologically-defined data are available, which would provide an objective evidence on how overactivation of these receptors could lead to motor neuron degeneration in ALS. Our current study demonstrates that in fully awake SOD1G93A rats, there are profound and spontaneous α-motoneuron-mediated electromyographic activities measured at the level of gastrocnemius muscle, which is absent in age-matched wild type rats. This activity is effectively suppressed by isoflurane, NGX424 (AMPA receptor antagonist) and baclofen (GABAB receptor agonist). These treatments have no suppressive effect of muscle denervation-induced muscle fibrillation. Immunofluorescence and western blot analyses of lumbar spinal cord in SODG93A rats showed sustained presence of AMPA receptors and a significant increase in spinal VGluT1/2expression during end-stage at the lumbar intermediate zone. These data suggest an active participation of AMPA receptors and VGluT1/2 in mediating glutamate release and binding in observed overactivation of interneurons and alpha motor neurons. Additionally, unilateral sciatic neurectomy reduced VGluT1 expression and thus, the decrease of the more downstream muscle fibrillation. Accordingly, therapeutics reducing excessive glutamate receptor-mediated overexcitation, such as inhibition of excitatory interneuron-mediated glutamate release, or potentiation of spinal neuronal inhibition, may be effective in modulating alpha motor neuron degeneration in ALS.