Glutamate is the major excitatory neurotransmitter in the central nervous system and so is critical for essentially all behaviors. However, overactivation of glutamate receptors, particularly during conditions of persistent metabolic and oxidative stress, can cause the degeneration of synapses and neuronal death. This excitotoxic process is believed to play an important role in a range of acute (stroke and traumatic brain and spinal cord injury) and chronic (Alzheimer's, Parkinson's, and Huntington's diseases) neurodegenerative conditions. Uncontrolled chronic psychological and/or physical stress may render neurons vulnerable to excitotoxicity by impairing the energy metabolism and compromising cellular ion homeostasis. Chronic elevations of glucocorticoids and diminished levels of neurotrophic factors such as brain-derived neurotrophic factor (BDNF) may play important roles in the pro-excitotoxic effect of chronic stress. On the other hand, mild intermittent stresses, such as physical exercise, cognitive stimulation, and dietary restriction may protect neurons against excitotoxicity by stimulating the expression of genes that encode neuroprotective proteins such as BDNF and heat shock proteins. A better understanding of the cellular and molecular mechanisms by which both detrimental and beneficial types of stress affect neuronal vulnerability to excitotoxicity may lead to novel interventions for the prevention and treatment of a range of neurodegenerative conditions.
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