Driven to decay: Excitability and synaptic abnormalities in amyotrophic lateral sclerosis

Brain Res Bull. 2018 Jun;140:318-333. doi: 10.1016/j.brainresbull.2018.05.023. Epub 2018 Jun 2.

Abstract

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron (MN) disease and is clinically characterised by the death of corticospinal motor neurons (CSMNs), spinal and brainstem MNs and the degeneration of the corticospinal tract. Degeneration of CSMNs and MNs leads inexorably to muscle wastage and weakness, progressing to eventual death within 3-5 years of diagnosis. The CSMNs, located within layer V of the primary motor cortex, project axons constituting the corticospinal tract, forming synaptic connections with brainstem and spinal cord interneurons and MNs. Clinical ALS may be divided into familial (∼10% of cases) or sporadic (∼90% of cases), based on apparent random incidence. The emergence of transgenic murine models, expressing different ALS-associated mutations has accelerated our understanding of ALS pathogenesis, although precise mechanisms remain elusive. Multiple avenues of investigation suggest that cortical electrical abnormalities have pre-eminence in the pathophysiology of ALS. In addition, glutamate-mediated functional and structural alterations in both CSMNs and MNs are present in both sporadic and familial forms of ALS. This review aims to promulgate debate in the field with regard to the common aetiology of sporadic and familial ALS. A specific focus on a nexus point in ALS pathogenesis, namely, the synaptic and intrinsic hyperexcitability of CSMNs and MNs and alterations to their structure are comprehensively detailed. The association of extramotor dysfunction with neuronal structural/functional alterations will be discussed. Finally, the implications of the latest research on the dying-forward and dying-back controversy are considered.

Keywords: Dendrite; Motor neuron disease; SOD1; Spine density; TDP-43.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Amyotrophic Lateral Sclerosis / physiopathology*
  • Animals
  • Humans
  • Neurons / physiology
  • Synapses / physiology*