Synaptic and Neuroglial Pathobiology in Acute and Chronic Neurological Disorders

Abstract

Pathology at the molecular and cellular level is the fundamental basis of disorders that effect the brain or spinal cord of humans. A pathophysiological event can target specific molecules and groups of cells, causing neuronal dysfunction and degeneration and resulting in acute and chronic neurological and behavioral disabilities ranging from memory loss to paralysis. For example, Alzheimer’s disease (AD) is associated with loss of forebrain neurons and the formation of brain lesions consisting of abnormal deposits of glial- or -neuronal generated amyloid β protein, possibly in response to gene mutations, synaptic perturbations, oxidative stress, or neuronal cytoskeletal defects (1–5). The degeneration of motor neurons in amyotrophic lateral sclerosis (ALS) is associated with impairments in glutamate reuptake by astroglia (6,7), gene mutations in superoxide dismutase- 1 (8), and abnormal apoptosis of motor neurons that appears to be mediated by programmed cell death mechanisms (9,10). The nerve cell damage in adults and children that have experienced cardiac arrest, asphyxiation, strokes, and head or spinal cord trauma may be caused by failure of astroglial glutamate transport, excessive stimulation of glutamate receptors, abnormal activation or impaired function of intracellular signaling pathways, toxic generation of free oxygen radicals, and structural damage to target molecules within selectively vulnerable populations of neurons (11). Epidemiological studies reveal the impact that neurodegenerative disorders have on our society. For example, AD affects ~4 million adults (most are>65-yr-of-age) and is the fourth-leading cause of death in the United States, accounting for>100,000 deaths annually (12). ALS affects approx 30,000 Americans (4–6 people in 100,000) (13). Stroke is the third leading cause of death in industrialized populations and is a major cause of long term neurological disability (14).