Introduction

There is considerable evidence that neuronal death will result following the exposure of neurones or central nervous system (CNS) tissue to excitatory amino acids (EAA) either in vivo or in vitro (Choi, 1988). This toxicity appears to be mediated by overstimulation of neurones through activation of EAA receptors (‘excitotoxicity’) (Choi, 1988; Rothman, 1992). Several EAA such as glutamate and aspartate are candidate neurotransmitters at synapses of the corticospinal tracts, as well as at other synapses in the CNS (Young et al., 1983). These observations have been central to hypotheses suggesting that the neurodegenerative disorder amyotrophic lateral sclerosis (ALS), also known as motor neurone disease, could be associated with impaired glutamate function or excitotoxicity. ALS is a progressive disorder of unknown cause affecting motoneurones and descending spinal cord pathways.

At least five independent lines of evidence have been presented to suggest that ‘glutamatergic dysfunction’ or excitotoxicity may in part be responsible for the development of ALS. These lines of evidence include:

1. The association between exposure to known excitotoxins and the development of motoneuronopathies in humans and primates.

2. Observations that elevated concentrations of glutamate are present in the plasma and/or cerebrospinal fluid (CSF) of patients who have died with ALS.

3. Observations of reduced contents of glutamate and aspartate in spinal cords and brains of patients who have died with ALS.

4. Evidence of decreased glutamate uptake by synaptosomes obtained from spinal cords and brains of ALS patients.