We have focused our studies on the mechanisms by which neurotransmitters become neurotoxins and the role of these toxins in the death of neurons characteristic of neurodegenerative disorders such as Alzheimer's disease, Huntington's disease, Parkinson's disease, lathyrism, etc. We have shown that cerebellar-neurons cultured from neonatal rats express several subtypes of glutamate receptor, including the N-methyl-D-aspartate (NMDA) receptor. When this receptor is occupied by an appropriate agonist, a receptor-gated channel opens, permitting sodium and calcium influx. However, in the healthy brain this channel is normally blocked by magnesium in a voltage-dependent manner, i.e, magnesium prevents ion influx through the channel at normal membrane potential. Under physiological conditions, the NMDA channel may only permit ion flow in response to high-frequency stimulation. We have shown that the magnesium block is relieved when neurons partially depolarize in response to reduced energy levels in the neuron; decreases in adenine nucleotide levels due to glucose starvation, oxygen deprivation, or metabolic poisons cause sufficient depolarization to relieve the magnesium block of the channel. Thus, when neuronal energy levels are compromised, endogenous agonists such as glutamate can persistently open the NMDA channel resulting in excess ion influx; the increased energy demands by the pumps involved in maintaining ion gradients cannot be met in the energy-poor neurons, and neuronal death ensues via a mechanism not yet understood. Our results provide experimental evidence for a mechanism which may trigger the transition of endogenous glutamate from neurotransmitter to neurotoxin; this mechanism may have important implications for a variety of neurodegenerative disorders.
