Neurons are able to restore their activity when challenged by external or internal perturbations. This type of homeostatic plasticity is important for the maintenance of neuronal or network stability during development and normal brain function. During homeostatic synaptic plasticity, chronic suppression of neuronal activity leads to a compensatory increase in synaptically distributed AMPA receptors (AMPARs) and the intensity of synaptic currents. AMPARs are heterotetrameric channels composed of GluA1-4 subunits. Compared to regular GluA2-containing AMPARs that permit only sodium, GluA2-lacking receptors are permeable to both sodium and calcium. GluA2-lacking, calcium-permeable AMPARs (Cp-AMPARs) are formed during neuronal inhibition and are required for the expression of homeostatic plasticity. However, the molecular mechanisms underlying Cp-AMPAR biogenesis during homeostatic regulation remain largely unknown. We have discovered that miR124, a brain-enriched microRNA (miRNA), suppresses GluA2 translation by targeting the 3'-UTR of GluA2 mRNA, leading to the formation of Cp-AMPARs. Importantly, we found that inhibition of miR124 function abolished inactivity-induced homeostatic regulation. Therefore, we hypothesize that inactivity up-regulates miR124 expression via epigenetic modification, resulting in GluA2 translational suppression and formation of Cp-AMPARs, thus leading to the expression of homeostatic synaptic plasticity. In this proposed study, we will investigate the molecular details in the regulation of miR124 expression and the role of miR124 in GluA2 expression and Cp-AMPAR biogenesis. Furthermore, we will investigate the epigenetic control of miR124 expression by the inhibitory transcription factor EVI and its co-factor, the deacetylase HDAC1. More importantly, we will investigate the involvement of miRNA and the EVI transcriptional complex in the expression of homeostatic plasticity in vitro and in vivo. These studies will shed new light on our understanding of neural functional homeostasis and network stability. Elucidation of Cp-AMPAR biogenesis will also have an impact on clinical studies, as Cp-AMPARs have been implicated in disorders such as stroke, ALS and drug addiction.

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Neurons are able to restore their activity when challenged by external or internal perturbations. This type of homeostatic plasticity is important in the maintenance of neuronal or network stability during development and normal brain function. The proposed research will identify mechanisms by which the microRNA miR124 suppresses AMPA receptor GluA2 mRNA translation, leading to the formation of GluA2-lacking AMPA receptors, which are required for homeostatic plasticity. Findings from these studies will provide a better understanding of neuronal network stability and brain function.

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National Institute of Mental Health (NIMH)
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Synapses, Cytoskeleton and Trafficking Study Section (SYN)
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Driscoll, Jamie
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Boston University
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Shentu, Yang-Ping; Huo, Yuda; Feng, Xiao-Long et al. (2018) CIP2A Causes Tau/APP Phosphorylation, Synaptopathy, and Memory Deficits in Alzheimer's Disease. Cell Rep 24:713-723
Hastings, Margaret H; Man, Heng-Ye (2018) Synaptic Capture of Laterally Diffusing AMPA Receptors - An Idea That Stuck. Trends Neurosci 41:330-332
Khatri, Natasha; Gilbert, James P; Huo, Yuda et al. (2018) The Autism Protein Ube3A/E6AP Remodels Neuronal Dendritic Arborization via Caspase-Dependent Microtubule Destabilization. J Neurosci 38:363-378
Keaveney, Marianna K; Tseng, Hua-An; Ta, Tina L et al. (2018) A MicroRNA-Based Gene-Targeting Tool for Virally Labeling Interneurons in the Rodent Cortex. Cell Rep 24:294-303
Wang, Guan; Li, Shaomin; Gilbert, James et al. (2017) Crucial Roles for SIRT2 and AMPA Receptor Acetylation in Synaptic Plasticity and Memory. Cell Rep 20:1335-1347
Gauthier, Jamie M; Lin, Amy; Nic Dhonnchadha, Bríd Á et al. (2017) Environmental enrichment facilitates cocaine-cue extinction, deters reacquisition of cocaine self-administration and alters AMPAR GluA1 expression and phosphorylation. Addict Biol 22:152-162
Gilbert, James; Man, Heng-Ye (2017) Fundamental Elements in Autism: From Neurogenesis and Neurite Growth to Synaptic Plasticity. Front Cell Neurosci 11:359
Kohman, Richie E; Cha, Susie S; Man, Heng-Ye et al. (2016) Light-Triggered Release of Bioactive Molecules from DNA Nanostructures. Nano Lett 16:2781-5
Gilbert, James; Shu, Shu; Yang, Xin et al. (2016) ?-Amyloid triggers aberrant over-scaling of homeostatic synaptic plasticity. Acta Neuropathol Commun 4:131
Gilbert, James; Man, Heng-Ye (2016) The X-Linked Autism Protein KIAA2022/KIDLIA Regulates Neurite Outgrowth via N-Cadherin and ?-Catenin Signaling. eNeuro 3:

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