1. The molecular mechanism underlying long-term synaptic depression. The strength of synaptic transmission can change through synaptic plasticity. Long-lasting forms of synaptic plasticity (such as long-term potentiation and long-term depression of synaptic transmission) are important cellular mechanisms underlying information storage in the brain and the establishment of proper neural circuits during development. In this project, we investigate the mechanism underlying the induction of long-term depression of synaptic transmission (LTD). Our group previously reported that caspases are activated during LTD to induce AMPA receptor internalization. During the past few years, we have been investigating the mechanism by which caspases regulated AMPA receptor trafficking, We found that macroautophagy(autophagy hereinafter) is a mediator of caspases in LTD. Autophagy is a cellular process for the degradation of cytoplasmic components and organelles via lysosomes. Autophagy is also essential for the development and function of synapses. It enables the developmental pruning of dendritic spines (subcellular structures accommodating postsynaptic components), and regulates presynaptic structure, dopamine release, and degradation of postsynaptic receptors. Anomalous autophagy is associated with brain disorders. Autophagy is orchestrated by more than 30 autophagy-related (Atg) proteins and multiple signaling pathways. Mechanistic target of rapamycin complex 1 (mTORC1) is the best-characterized autophagy regulator in mammalian cells. Using mTOR inhibitors and knockout mice with deficient autophagy, we found that autophagic flux changes during LTD and this in turn leads to AMPA receptor endocytosis. During this reporting period, we investigated how autophagy interacts with the endosomal trafficking of AMPA receptors and the influence of autophagy on the behavior of mice. 2. The role of dysbindin-1 in synaptic physiology. Dysbindin-1 is a coiled-coil domain containing protein, initially discovered as a dystrophin-binding protein and later found to be one of eight subunits of biogenesis of lysosome-related organelles complex 1 (BLOC-1). The postmortem brains of individuals with schizophrenia have reduced dysbindin-1 proteins and mRNAs. Our earlier work shows that dysbindin-1 contributes to the establishment of neuronal connectivity during adolescence by regulating the growth of dendritic protrusions, including dendritic spines (tiny dendritic protrusions where excitatory synapses are formed) and filopodia (long, thin protrusions that are precursors of dendritic spines in young neurons). During this review period, we investigated the role of dysbindin-1 in psychogenic stress-induced synaptic alterations. We conducted electrophysiological recordings in brain slices taken from dysbindin-1 mutant and wild-type mice. We found that after mild psychogenic stress, synaptic plasticity can be more easily induced in dysbindin-1 mutant mice than in wild-type mice. Because of this reduced synaptic plasticity threshold, the social behavior of dysbindin-1 mutant mice is altered by mild stress that has no significant effect on wild-type mice. We applied pharmacological inhibitors of various neurotransmitters to examine the mechanism underlying this phenomenon.

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Support Year
13
Fiscal Year
2019
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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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