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Inhibitory Synaptic Regulation of Motoneurons: A New Target of Disease Mechanisms in Amyotrophic Lateral Sclerosis

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Abstract

Amyotrophic lateral sclerosis (ALS) is the third most common adult-onset neurodegenerative disease. It causes the degeneration of motoneurons and is fatal due to paralysis, particularly of respiratory muscles. ALS can be inherited, and specific disease-causing genes have been identified, but the mechanisms causing motoneuron death in ALS are not understood. No effective treatments exist for ALS. One well-studied theory of ALS pathogenesis involves faulty RNA editing and abnormal activation of specific glutamate receptors as well as failure of glutamate transport resulting in glutamate excitotoxicity; however, the excitotoxicity theory is challenged by the inability of anti-glutamate drugs to have major disease-modifying effects clinically. Nevertheless, hyperexcitability of upper and lower motoneurons is a feature of human ALS and transgenic (tg) mouse models of ALS. Motoneuron excitability is strongly modulated by synaptic inhibition mediated by presynaptic glycinergic and GABAergic innervations and postsynaptic glycine receptors (GlyR) and GABAA receptors; yet, the integrity of inhibitory systems regulating motoneurons has been understudied in experimental models, despite findings in human ALS suggesting that they may be affected. We have found in tg mice expressing a mutant form of human superoxide dismutase-1 (hSOD1) with a Gly93 → Ala substitution (G93A-hSOD1), causing familial ALS, that subsets of spinal interneurons degenerate. Inhibitory glycinergic innervation of spinal motoneurons becomes deficient before motoneuron degeneration is evident in G93A-hSOD1 mice. Motoneurons in these ALS mice also have insufficient synaptic inhibition as reflected by smaller GlyR currents, smaller GlyR clusters on their plasma membrane, and lower expression of GlyR1α mRNA compared to wild-type motoneurons. In contrast, GABAergic innervation of ALS mouse motoneurons and GABAA receptor function appear normal. Abnormal synaptic inhibition resulting from dysfunction of interneurons and motoneuron GlyRs is a new direction for unveiling mechanisms of ALS pathogenesis that could be relevant to new therapies for ALS.

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Acknowledgements

This work was supported by grants from the U.S. Public Health Service, National Institutes of Health, National Institute on Aging (R01-AG016282), and National Institute of Neurological Disorders and Stroke (R01-NS034100, R01-NS065895, and R01-NS052098).

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  1. Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD, 21205-2196, USA

    Lee J. Martin & Qing Chang

  2. Pathobiology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21205-2196, USA

    Lee J. Martin

  3. Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205-2196, USA

    Lee J. Martin

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Correspondence to Lee J. Martin.

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Martin, L.J., Chang, Q. Inhibitory Synaptic Regulation of Motoneurons: A New Target of Disease Mechanisms in Amyotrophic Lateral Sclerosis. Mol Neurobiol 45, 30–42 (2012). https://doi.org/10.1007/s12035-011-8217-x

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