Synaptic Deprivation and Age‐Related Vulnerability to Hypoxic‐Ischemic Neuronal Injury

Abstract

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.