This year, we revealed a relationship between long-term depression (LTD), mitochondria and caspases. In this study we show that activation of caspase-3 through mitochondria is actually required for long-term depresssion (LTD) and for the internalization of AMPA receptor GluR2 in mouse hippocampal neurons. We report that regulatory factors and executors of apoptosis play a role in the molecular mechanism of synaptic plasticity. We closely examined the mitochondrial pathway, which is mediated by caspase-9 and caspase-3, as being an essential part of LTD but not LTP. We show that caspase-3 knockout hippocampal slices are defective in LTD while LTP remains unaffected. This is compelling evidence for the specificity of caspase-3 in one form of synaptic modification. The importance of the mitochondrial signaling pathway in LTD is related with its critical role in inducible GluR2 AMPA receptor internalization. Caspases-3 and -9 are crucial for LTD and GluR2 trafficking, but not for LTP. In addition, short-term glutamate receptor stimulation sufficient to induce AMPA receptor redistribution and synaptic modification causes caspase-3 activation that is transient and mild, as compared with a conventional factor that cause massive apoptosis. This mild activation of caspase-3 by short-duration glutamate receptor stimulation was unrelated with increased cell death, a strong indicator that caspase-3 does not inevitably lead to apoptosis. It is believed that the complex morphology of neurons could allow for localized activation of caspases, so that spines and dendrites could be targeted for functional attrition and structural elimination without killing the rest of the cell.

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U.S. National Institute of Mental Health
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Hu, Zhonghua; Li, Zheng (2017) miRNAs in synapse development and synaptic plasticity. Curr Opin Neurobiol 45:24-31
Shen, Hongmei; Li, Zheng (2016) miRNAs in NMDA receptor-dependent synaptic plasticity and psychiatric disorders. Clin Sci (Lond) 130:1137-46
Ni, Ting; Wei, Gang; Shen, Ting et al. (2015) MitoRCA-seq reveals unbalanced cytocine to thymine transition in Polg mutant mice. Sci Rep 5:12049
Almeida-Suhett, Camila P; Prager, Eric M; Pidoplichko, Volodymyr et al. (2015) GABAergic interneuronal loss and reduced inhibitory synaptic transmission in the hippocampal CA1 region after mild traumatic brain injury. Exp Neurol 273:11-23
Han, Meng-Hsuan J; Hu, Zhonghua; Chen, Cai Yun et al. (2014) Dysbindin-associated proteome in the p2 synaptosome fraction of mouse brain. J Proteome Res 13:4567-80
Almeida-Suhett, Camila P; Li, Zheng; Marini, Ann M et al. (2014) Temporal course of changes in gene expression suggests a cytokine-related mechanism for long-term hippocampal alteration after controlled cortical impact. J Neurotrauma 31:683-90
Liu, Xing; Gu, Qin-Hua; Duan, Kaizheng et al. (2014) NMDA receptor-dependent LTD is required for consolidation but not acquisition of fear memory. J Neurosci 34:8741-8
Jia, Jie-Min; Zhao, Jun; Hu, Zhonghua et al. (2013) Age-dependent regulation of synaptic connections by dopamine D2 receptors. Nat Neurosci 16:1627-36
Han, Meng-Hsuan; Jiao, Song; Jia, Jie-Min et al. (2013) The novel caspase-3 substrate Gap43 is involved in AMPA receptor endocytosis and long-term depression. Mol Cell Proteomics 12:3719-31
Jiao, Song; Li, Zheng (2011) Nonapoptotic function of BAD and BAX in long-term depression of synaptic transmission. Neuron 70:758-72

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