Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the progressive and selective death of motor neurons in the motor cortex, brainstem, and spinal cord. The only therapy with proven efficacy for ALS patients is a treatment with riluzole that offers patients a moderate increase in survival. Riluzole interferes with excitotoxicity, which is neuronal death caused by overstimulation of glutamate transporters. The high sensitivity of motor neurons to excitotoxicity is further illustrated by the observation that a number of exogenous toxic substances (excitotoxins) that stimulate
glutamate receptors result in selective motor neuron death. This selective vulnerability of motor neurons to excitotoxic insults is due to their poor calcium buffering capacity in combination with the expression of calcium-permeable AMPA type of glutamate receptors. The AMPA receptor subunit responsible for calcium impermeability, GluR2, is expressed at lower levels, and RNA editing of GluR2 required for calcium impermeability is diminished in motor neurons of ALS patients. Not only calcium permeability of AMPA receptors but also glutamate transport into neighboring astrocytes plays an important role in ALS. Decreased levels of glutamate transporters are present in ALS patients and ALS animal models, implying an increased vulnerability to glutamate. This chapter aims to provide an overview of the known players and their interactions in the field of excitotoxic motor neuron death and in the context of ALS.