Li Z, Jo J, Jia JM, Lo SC, Whitcomb DJ, Jiao S, Cho K, Sheng M. Caspase-3 activation via mitochondria is required for long-term depression and AMPA receptor internalization. Cell. 2010 May 28;141(5):859-71. PubMed.
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Boise State University
The recent study by Li et al. is an intriguing one that provides a mechanism for long-term depression (LTD) in neurons. LTD is a phenomenon by which neurons lose AMPA receptors from the post-synaptic membrane, leading to a diminished ability to activate this excitatory pathway. Thus, LTD is one important mechanism underlying plasticity, a vital process for learning and development. Although LTD has been well characterized, the exact mechanism of this process has remained elusive. In this study, the authors use both pharmacological and molecular approaches to indicate the activation of caspases (namely, caspase-3 and -9) is critical for the internalization of AMPA receptors and, therefore, the process of LTD. Moreover, the authors demonstrate that Akt1 is a key player in this process. Akt1 has a role in preventing LTD by inhibiting the activity of GSK3β, whose function is critical for LTD. Li et al. now show that caspase activation leads to Akt1 cleavage and inactivation, thus providing a mechanism by which caspase-3 initiates LTD.
What makes this study even more provocative is that activation of caspases in this manner mediates a physiological function, and does not lead to overt cell death by apoptosis. In the developing brain, anywhere from 20-80 percent of neurons die through apoptosis as the CNS is sculpted to its final appearance and function (Oppenheim, 1991). For years it was believed that in the adult brain, this pathway remains inactive (for good reason) except during disease states whereby activation of caspases could contribute to neurodegeneration (i.e., Alzheimer disease; see Rohn, 2010). However, Li et al. now provide strong experimental evidence that caspases are playing a non-apoptotic role in neurons and in fact are critical for synaptic plasticity. Previous studies have suggested additional roles in neurons beyond executing apoptosis. For example, caspase activation may be required for neuronal differentiation, dispersal, and correct morphology (Rohn et al., 2004; Yan et al., 2001). Although caspases are indispensable for the proper execution of apoptosis, the study by Li et al. clearly shows that the actions of caspases can “cut” both ways—either physiologically in carrying out LTD, or pathologically when activated during certain neurodegenerative diseases.
References:
Oppenheim RW. Cell death during development of the nervous system. Annu Rev Neurosci. 1991;14:453-501. PubMed.
Rohn TT. The role of caspases in Alzheimer's disease; potential novel therapeutic opportunities. Apoptosis. 2010 Nov;15(11):1403-9. PubMed.
Rohn TT, Cusack SM, Kessinger SR, Oxford JT. Caspase activation independent of cell death is required for proper cell dispersal and correct morphology in PC12 cells. Exp Cell Res. 2004 Apr 15;295(1):215-25. PubMed.
Yan XX, Najbauer J, Woo CC, Dashtipour K, Ribak CE, Leon M. Expression of active caspase-3 in mitotic and postmitotic cells of the rat forebrain. J Comp Neurol. 2001 Apr 23;433(1):4-22. PubMed.
The neurotrophin receptor p75 has been reported to facilitate NMDAR-dependent long-term depression of Schaeffer collateral-CA1 synapses (Woo et al., 2005) and (in p75-mediated apoptosis of various cell types including neurons) to induce activation of caspase-3. The lack of LTD of Schaeffer collateral-CA1 synapses in caspase-3 knockout mice observed by Li et al. should correlate with the lack of LTD in p75 knockout mice described by Woo et al., indicating that caspase-3 is essential for p75-induced LTD and that LTD of Schaeffer collateral-CA1 synapses is under the control of p75.
References:
Woo NH, Teng HK, Siao CJ, Chiaruttini C, Pang PT, Milner TA, Hempstead BL, Lu B. Activation of p75NTR by proBDNF facilitates hippocampal long-term depression. Nat Neurosci. 2005 Aug;8(8):1069-77. PubMed.
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