title: Excitotoxicity in ALS: Overstimulation, or overreaction?
abstract: Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disease that results in motor dysfunction and death, generally from respiratory failure. 90% of ALS cases are sporadic with no known cause. Familial cases have been linked with mutations in several disparate classes of genes, including those involved in DNA/RNA metabolism, protein misfolding, oxidative stress and the cytoskeleton, leading to the proposition that ALS could be a multi-factorial disease. However, alterations in excitability have been reported in all types of ALS cases, and may be a common disease mechanism predisposing neurons to degeneration. Excitotoxicity has long been suspected as a mediator in the disease process, and may arise from changes in synaptic inputs, or alterations in the excitability of the neurons being stimulated. Although the glutamatergic system is widely recognised as a therapeutic avenue with the potential to extend lifespan and delay disease onset, the causes of altered excitability in ALS are currently unclear and warrant further investigation. This article reviews current evidence of alterations to excitatory and inhibitory signalling in the cortex and spinal cord, and in the intrinsic excitability of motor neurons, in ALS.
authors.affiliation: Wicking Dementia Research and Education Centre, Faculty of Health, University of Tasmania, Hobart, Tasmania 7000, Australia. Electronic address: kingae@utas.edu.au.
authors.forename: Anna E
authors.initials: AE
authors.lastname: King
authors.affiliation: Wicking Dementia Research and Education Centre, Faculty of Health, University of Tasmania, Hobart, Tasmania 7000, Australia.
authors.forename: Adele
authors.initials: A
authors.lastname: Woodhouse
authors.affiliation: Wicking Dementia Research and Education Centre, Faculty of Health, University of Tasmania, Hobart, Tasmania 7000, Australia.
authors.forename: Matthew T K
authors.initials: MT
authors.lastname: Kirkcaldie
authors.affiliation: Wicking Dementia Research and Education Centre, Faculty of Health, University of Tasmania, Hobart, Tasmania 7000, Australia.
authors.forename: James C
authors.initials: JC
authors.lastname: Vickers
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology
chemical_list: D018698:Glutamic Acid
keywords: ALS; EAAT2; Excitability; GABA; Glutamate; Glycine; Interneuron; Motor neuron disease