Evidence for Synaptic Apoptosis

• Published in: Experimental neurology Vol. 153; no. 1; pp. 35 - 48
• Main Authors: Mattson, Mark P., Keller, Jeffrey N., Begley, James G.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01.09.1998; Elsevier
• Subjects: Alzheimer's disease; Animals; Annexin A5 - metabolism; Apoptosis - physiology; Biological and medical sciences; Biomarkers; Blotting, Western; Calcium - metabolism; caspase; Caspase 3; Caspases; Cell Nucleus - drug effects; Cell Nucleus - ultrastructure; Cell-Free System; Cells, Cultured; Cysteine Endopeptidases - metabolism; Cysteine Proteinase Inhibitors - pharmacology; dendritic spines; Development. Senescence. Regeneration. Transplantation; Female; Fundamental and applied biological sciences. Psychology; glutamate; Glutamic Acid - pharmacology; Hippocampus - cytology; Hippocampus - physiology; Hippocampus - ultrastructure; Membrane Potentials - physiology; mitochondrial transmembrane potential; Neurons - physiology; Neurons - ultrastructure; oxidative stress; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species - metabolism; staurosporine; Synapses - physiology; Synapses - ultrastructure; synaptosomes; Synaptosomes - physiology; Synaptosomes - ultrastructure; Vertebrates: nervous system and sense organs; staurosporine; synaptosomes; mitochondrial transmembrane potential; Alzheimer's disease; dendritic spines; glutamate; oxidative stress; caspase; Oxidative stress; Rat; Rodentia; Nervous system; Glutamate; Mechanism; Vertebrata; Synapse; Synaptosome; Mammalia; Neuron; Cell death; Animal; Apoptosis
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1006/exnr.1998.6863

Increasing evidence indicates that neurons die by apoptosis, an active form of cell death involving a relatively stereotyped series of biochemical changes that culminate in nuclear fragmentation, in many different developmental and pathophysiological settings. In contrast to most other cell types, neurons have elaborate morphologies with complex neuritic arbors that often extend great distances from the cell body. Neuronal death signals are likely to be activated at remote synaptic sites and, indeed, overactivation of glutamate receptors and underactivation of trophic factor receptors are implicated in neurodegenerative disorders. We now report that biochemical changes consistent with apoptosis are engaged locally in synapses. Exposure of cortical synaptosomes to staurosporine and Fe2+resulted in loss of membrane phospholipid assymetry, caspase activation, and mitochondrial alterations (membrane depolarization, calcium overload, and oxyradical accumulation) characteristic of apoptosis. The caspase inhibitor zVAD-fmk prevented mitochondrial membrane depolarization in synaptosomes. Studies of the effects of cytosolic extracts from synaptosomes exposed to apoptotic insults, on isolated nuclei, showed that signals capable of inducing nuclear apoptosis are generated locally in synapses. Exposure of cultured hippocampal neurons to staurosporine and glutamate resulted in caspase activation and mitochondrial membrane depolarization in dendrites, and zVAD-fmk prevented the membrane depolarization. Glutamate-induced increases in caspase activity were first observed in dendrites and later in the cell body, and focal application of glutamate to individual dendrites resulted in local activation of caspases. Collectively, the data demonstrate that apoptotic biochemical cascades can be activated locally in synapses and dendrites and suggest a role for such local apoptotic signals in synapse loss and neuronal death in neurodegenerative disorders that involve excessive activation of glutamate receptors.