Synaptic deprivation and age-related vulnerability to hypoxic-ischemic neuronal injury. A hypothesis.
Advanced age is associated with physiological changes, such as cerebral autoregulation dysfunction, atrial fibrillation, reduced cerebral blood flow, elevated blood pressure, and other changes. Stroke-related dementia is associated with brain loss principally due to strokes, and neuropathological examination of the brains of old people shows a direct correlation between the extent of brain loss and dementia. However, the exact mechanism of the age related vulnerability to hypoxic-ischemic neuronal injury remains unknown. The majority of synapses in the brain use excitatory amino acids as their neurotransmitter. Glutamate, a major endogenous excitatory amino acid required for normal physiological excitation, is also involved in the pathophysiology of hypoxic-ischemic neuronal injury. The N-methyl-D-aspartate (NMDA) glutamate receptor subtype plays a major role in mediating hypoxic-ischemic neuronal injury. NMDA receptors also mediate adaptive responses important for synaptic plasticity. This report explores the possible role of synaptic activity as a protective mechanism against neuronal cell death. Specifically, the role of NMDA receptors in neuronal plasticity by upregulating a survival pathway is discussed. Loss of a neuronal population that uses glutamate as its neurotransmitter leads to a loss of activity on the postsynaptic neurons or synaptic deprivation. Deprivation of excitatory amino acids on the postsynaptic neurons results in the failure of activity-dependent induced intrinsic survival pathways induced by NMDA receptors. The loss of neuroprotective intrinsic survival pathways increases the vulnerability of these neurons to more hypoxic-ischemic neuronal damage. Since cerebral infarction is also age related, this hypothesis provides a plausible explanation of how we become more vulnerable to hypoxic-ischemic neuronal injury as a function of age.
Marini
A M
AM
Departments of Neurology and Neuroscience, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
Choi
J
J
Labutta
R
R
D000367:Age Factors; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000187:drug effects / Q000378:metabolism*; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D017781:Genes, Immediate-Early / Q000187:drug effects / Q000502:physiology; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism; D016202:N-Methylaspartate / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009841:Oligonucleotides / Q000494:pharmacology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology*; D012307:Risk Factors; D013569:Synapses / Q000187:drug effects / Q000502:physiology*
D019208:Brain-Derived Neurotrophic Factor; D018690:Excitatory Amino Acid Agonists; D016328:NF-kappa B; D009841:Oligonucleotides; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate