2008 — 2012 |
Man, Hengye |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Homeostatic Regulation and Trafficking of Ampa Receptors At Single Synapses
[unreadable] DESCRIPTION (provided by applicant): In the central nervous system, a neuron receives a large number of synaptic inputs from many surrounding cells, with individual synapses acting independently of one another. Synaptic plasticity, which is essential for high brain functions including learning and memory, is a synapse autonomous event under physiological conditions. A large amount of data has shown that both Hebbian-type synaptic plasticity including long-term potentiation (LTP) and long-term depression (LTD), as well as non-Hebbian type homeostatic synaptic plasticity are expressed via regulation of synaptic AMPA receptor (AMPAR) abundance, often by vesicle-mediated receptor trafficking. Given the fact that plasticity is highly synapse specific, investigation of synapse specific, activity-dependent regulation of AMPAR expression will provide crucial insights in our understanding of synapse physiology and brain function. Furthermore, homeostatic plasticity has been studied only at the neuronal population level; if and how it is expressed at single synapses remains elusive. To address these issues, we have set up two experimental paradigms in neuronal culture, in which activity levels of identifiable single synapses are specifically regulated. We will investigate the cellular mechanisms by which AMPAR abundance is specifically regulated in response to activity changes at single synapses. PUBLIC HEALTH RELEVANCE: The application aims to understand the mechanisms by which the strength of intercellular communication is regulated in neurons. By investigating synapse specific, activity-dependent regulation of AMPAR expression, this study will provide crucial insights in our understanding of synapse physiology and brain function. [unreadable] [unreadable]
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2014 — 2018 |
Man, Hengye |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Molecular Mechanisms of Homeostatic Synaptic Plasticity @ Boston University (Charles River Campus)
DESCRIPTION (provided by applicant): 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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