Local pruning of dendrites and spines by caspase-3-dependent and proteasome-limited mechanisms.
Synapse loss occurs normally during development and pathologically during neurodegenerative disease. Long-term depression, a proposed physiological correlate of synapse elimination, requires caspase-3 and the mitochondrial pathway of apoptosis. Here, we show that caspase-3 activity is essential--and can act locally within neurons--for regulation of spine density and dendrite morphology. By photostimulation of Mito-KillerRed, we induced caspase-3 activity in defined dendritic regions of cultured neurons. Within the photostimulated region, local elimination of dendritic spines and dendrite retraction occurred in a caspase-3-dependent manner without inducing cell death. However, pharmacological inhibition of inhibitor of apoptosis proteins or proteasome function led to neuronal death, suggesting that caspase activation is spatially restricted by these "molecular brakes" on apoptosis. Caspase-3 knock-out mice have increased spine density and altered miniature EPSCs, confirming a physiological involvement of caspase-3 in the regulation of spines in vivo.
Department of Neuroscience, Genentech, South San Francisco, California 94080.
Ali
A
Ertürk
Yuanyuan
Y
Wang
Morgan
M
Sheng
D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D000367:Age Factors; D000818:Animals; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism*; D053453:Caspase 9 / Q000378:metabolism; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003712:Dendrites / Q000502:physiology / Q000648:ultrastructure*; D049229:Dendritic Spines / Q000502:physiology*; D004622:Embryo, Mammalian; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology* / Q000502:physiology; D009842:Oligopeptides / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013569:Synapses / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D013997:Time Factors
C582180:BV6 peptide; D015853:Cysteine Proteinase Inhibitors; D009842:Oligopeptides; D017382:Reactive Oxygen Species; C067713:lactacystin; D053148:Caspase 3; D053453:Caspase 9; D046988:Proteasome Endopeptidase Complex; D000111:Acetylcysteine
IAP; caspase-3; dendrite retraction; nonapoptotic; proteasome; spine elimination