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...

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Bibliographic Details
Published in:The Journal of neuroscience 2014-01, Vol.34 (5), p.1672-1688
Main Authors: Ertürk, Ali, Wang, Yuanyuan, Sheng, Morgan
Format: Article
Language:English
Subjects:
Acetylcysteine - analogs & derivatives
Acetylcysteine - pharmacology
Age Factors
Animals
Caspase 3 - genetics
Caspase 3 - metabolism
Caspase 9 - metabolism
Cells, Cultured
Cysteine Proteinase Inhibitors - pharmacology
Dendrites - physiology
Dendrites - ultrastructure
Dendritic Spines - physiology
Embryo, Mammalian
Enzyme Activation - drug effects
Enzyme Activation - genetics
Excitatory Postsynaptic Potentials - drug effects
Excitatory Postsynaptic Potentials - genetics
Gene Expression Regulation - drug effects
Hippocampus - cytology
In Vitro Techniques
Mice
Mice, Inbred C57BL
Mice, Transgenic
Neurons - cytology
Neurons - physiology
Oligopeptides - pharmacology
Proteasome Endopeptidase Complex - metabolism
Rats
Reactive Oxygen Species - metabolism
Signal Transduction - drug effects
Synapses - drug effects
Synapses - enzymology
Synapses - immunology
Time Factors
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Summary: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.
ISSN:0270-6474
1529-2401
DOI:10.1523/JNEUROSCI.3121-13.2014