Synaptic plasticity is an important process through which the nervous system responds to prior experience and adapts to environmental changes. The change in synaptic strength can be transient or last for long periods of time. The long-lasting form of synaptic plasticity plays a crucial role in the refinement of neuronal connections during development and in learning and memory. In mammals, NMDA receptor-dependent long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission are two major forms of long-lasting synaptic plasticity. AMPA receptor movement, both in and out of the synapse appears to be the cellular mechanism subserving the change of synaptic efficacy during LTP and LTD. Caspases are key proteolytic enzymes involved in programmed cell death or apoptosis and are grouped as either initiators or effectors that act on extrinsic (ligand binding) and intrinsic (mitochondria) pathways of apoptosis. The presence of active caspases was believed to lead irreversibly to cell death, and thus was a widely used marker of apoptotic cells. However, active caspases can be also detected in cells that are not destined to die, and it is now widely accepted that caspases can play non-apoptotic roles in various developmental and physiological contexts. In 2012, we reviewed the functions of caspases in altering synaptic transmission under both physiological and pathological conditions, and its relevance to cognition. In the past few years, studies from several groups collectively point to an essential function of caspases in synaptic plasticity, independent of neuronal cell death. Two initiator caspases, 1 and 9, and the effector caspase-3 are shown to regulate long lasting synaptic plasticity in hippocampal neurons. Our group provided compelling evidence that the induction of NMDA receptor-dependent LTD is critically dependent on caspase-3 activation, active caspase-3 is sufficient to induce synaptic depression, and that BAD and BAX induced mitochondrial release of cytochrome c plays a crucial role in activating caspase-3 in LTD. Synaptic plasticity is crucial for learning and memory. Consistent with their functions in LTD and LTP, caspase-3 and -1 have been reported to contribute to learning and memory as seen in zebra finch where caspase-3 is necessary for memory consolidation during birdsong learning. In addition, chronic brain infusion of a caspase-1 inhibitor in aged rats improves hippocampus dependent contextual memory. There are also emerging evidence that caspases are active in early stages of Alzheimers disease, and could mediate synapse dysfunction and loss before the advent of cell death and neurodegeneration. These new insights highlight the regulatory role of caspases in synaptic plasticity under both normal and pathological conditions. Despite the importance of caspases in synaptic plasticity, the mechanism by which caspases controls synaptic transmission is still unclear. In 2012, we collaborated with Dr. Sanford Markey (NIMH) to screen for caspase substrates potentially involved in LTD. Several proteins were found to be cleaved in neurons upon LTD induction. Proteolysis of these putative caspase substrates during LTD were confirmed by caspase cleavage assay, and the cleavage sites were determined by mutagenesis. We have generated caspase-resistant mutants, and started to test their effects on synaptic transmission. In addition to the mitochondria-caspase pathway, we have also investigated the role of dopamine D2 receptors (D2R) in synapse development. D2R plays a pivotal role in brain functions mainly by modulating synaptic transmission. D2R dysfunction in schizophrenia is well known. All antipsychotics antagonize D2R, but they have little effect on cognitive impairment, a core symptom of schizophrenia related to impaired interneuronal connections. The mechanisms underlying neuronal dysconnection in schizophrenia remain elusive. In 2012, by using both pharmacological and genetic manipulations of D2R activity, we find that D2R regulates dendritic spine morphogenesis, and that the effect of D2R overactivation on spines can be alleviated by antipsychotics blocking D2R. These findings provide evidence that D2R dysfunction in schizophrenia contributes to neuronal dysconnectivity and consequent cognitive impairment.

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Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2012
Total Cost
$569,310
Indirect Cost
Name
U.S. National Institute of Mental Health
Department
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Shen, Hongmei; Li, Zheng (2016) miRNAs in NMDA receptor-dependent synaptic plasticity and psychiatric disorders. Clin Sci (Lond) 130:1137-46
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
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; 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
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
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
Cleland, M M; Norris, K L; Karbowski, M et al. (2011) Bcl-2 family interaction with the mitochondrial morphogenesis machinery. Cell Death Differ 18:235-47
Li, Zheng; Jo, Jihoon; Jia, Jie-Min et al. (2010) Caspase-3 activation via mitochondria is required for long-term depression and AMPA receptor internalization. Cell 141:859-71