Development of hyperexcitability in synaptic activity of spinal motoneurons in mutant SOD1 (G93A) mice

Project: Research project

Project Details


This project studies one important pathogenic mechanism, excitotoxicity, in a neurodegenerative disease amyotrophic Lateral Sclerosis (ALS). It is known that extra glutamate causes over-excitation and death of ALS motoneurons. Reducing this hyperexcitability with riluzone is so far the only effective therapy for ALS although its efficiency is very limited. The hyperexcitability in intrinsic firing has been observed in neonatal ALS animal model, mutant SOD1 mouse (mutation of superoxide dismutase 1 in glycine 93 to alanine, mSOD1G93A). However, we recently demonstrated that an adaptation occurs and makes this hyperexcitation return to normal level when the mice become adult. However, we also found synaptic activity in these adult mSOD1G93A motoneurons is hyperactive. These synaptic hyperexcitability is expressed at both sub- and supra- threshold levels of motor activity, seen as increased synaptic potential and the increased repetitive motor firing.
In this project, we will study the developmental profile of the hyperexctability in mSOD1G93A motoneurons. The experiments will be performed in mSOD1G93A mice at four different ages, at which the distinctive hallmarks of the disease are well established. We will evaluate several electrical activities of motoneurons, including fast excitatory postsynaptic potentials (fast EPSPs), NMDA receptor mediated oscillation of membrane potential, short-term synaptic/system plasticity, and intrinsic firing to determine their pattern switch and severity in relation with age. Selective agonist/antagonist, and modulators will also be tested to reveal the underlying cellular components responsible for the hyperexcitability. The measurement will be taken with a new technique we designed recently, which allows stable recording of the neural activity from intact whole spinal cord for several hours. Completion of this project will reveal more detailed mechanism of the excitotoxicity and may provide new therapeutic strategy on ALS.
Effective start/end date8/1/157/31/19


  • ALS Association (16-IIP-277)

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