Editors' ChoiceNeuroscience

Depressed About Caspases?

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Science Signaling  08 Jun 2010:
Vol. 3, Issue 125, pp. ec170
DOI: 10.1126/scisignal.3125ec170

Long-lasting changes in the efficacy of glutamatergic synaptic function can be effected through changes in the number of AMPA-type glutamate receptors (see Bateup and Sabatini). For instance, N-methyl-D-aspartate (NMDA)–type glutamate receptor–dependent long-term depression (LTD) in the CA1 region of the hippocampus involves the internalization of synaptic AMPA receptors. Intriguingly, Li et al. found that this form of synaptic plasticity depended on the activity of caspase-3, a cysteine protease known for its role in apoptosis. A comparison of the effects of peptide inhibitors active against different caspases indicated that inhibition of caspases-3 and -7, or -9, blocked LTD in rat hippocampal slices without affecting long-term potentiation (LTP) of synaptic function. Overexpression of XIAP (X chromosome–linked inhibitory apoptosis protein), which inhibits caspases-3, -7, and -9, or Bcl-xL, which prevents mitochondrial release of proapoptotic factors, such as cytochrome c, that lead to activation of caspase-9 and caspase-3, blocked LTD—but not LTP—in hippocampal slice cultures. LTD was also blocked by overexpression of a mutant form of Akt that is resistant to cleavage by caspase-3. Analyses of hippocampal slices from mice lacking caspase-3 revealed a specific deficit in LTD. Exposure to peptide inhibitors of caspases-3 and -7, or -9; overexpression of XIAP or Bcl-xL; or caspase-3 knockout all inhibited NMDA-induced internalization of AMPA receptors. NMDA treatment of cultured hippocampal neurons led to transient increases in cytosolic cytochrome c and in activation of caspase-3. The NMDA-mediated activation of caspase-3 was of lesser magnitude than that elicited by staurosporine, which induces neuronal apoptosis, and was not associated with neuronal death. The authors thus propose that elements of the mitochondrial apoptosis pathway are used to mediate LTD.

Z. Li, J. Jo, J.-M. Jia, S.-C. Lo, D. J. Whitcomb, S. Jiao, K. Cho, M. Sheng, Caspase-3 activation via mitochondria is required for long-term depression and AMPA receptor internalization. Cell 141, 859–871 (2010). [PubMed]

H. S. Bateup, B. L. Sabatini, For synapses, it’s depression not death. Cell 141, 750–752 (2010). [PubMed]

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