Brain derived neurotrophic factor (BDNF) is a key player that governs neuronal survival, differentiation and synaptic plasticity via activation of the TrkB receptor. Deficiency as well as exacerbation of BDNF-TrkB signaling is implicated in many human brain disorders, represented by mental impairment and epilepsy respectively. Our long-term goal is to elucidate molecular mechanisms that control BDNF production and BDNF-TrkB function in normal and pathological plasticity, which has important impact in developing novel strategies against diseases that involve BDNF dysfunction. Due to the pleiotropic functions of BDNF, expression of BDNF is tightly regulated in response to neuronal activity changes. Although BDNF transcription is subjected to sophisticated regulation, it could not explain the distinct temporal profiles of BDNF protein and mRNA upon neuronal activation and how the diffusible BDNF protein achieves local and synapse-selective modulation. The discovery of neuronal activity-stimulated dendritic transport of BDNF mRNA raises an intriguing possibility that BDNF may be locally translated in dendrites/synapse in response to neuronal activity changes, which offers a novel means to control long term synaptic modulation. Interestingly, regardless which promoter drives BDNF transcription, the 3'end of the BDNF transcript is processed at two alternative poly- adenylation sites, generating either a short or a long 3'untranslated region (3'UTR). The most recent studies revealed that while the short 3'UTR restricts BDNF mRNA in the neuronal soma, the long 3'UTR targets the BDNF mRNA into dendrites, which in turn governs normal synapse development and function. Our preliminary studies suggest that neuronal activity indeed regulates BDNF translation via the distinct 3'UTRs in the somatal and dendritic compartments, and identified miRNAs that differentilaly target the BDNF 3'UTRs. However, molecular mechanisms and synaptic signals controlling BDNF translation still remain elusive, which is a key issue for developing novel means to control BDNF-TrkB function. Moreover, despite the essential role of the BDNF long 3'UTR in normal synapse development as shown in our recent report, how 3'UTR-mediated regulation of BDNF may impact epileptogenesis remains uncovered. We hypothesize that translation regulation of BDNF by miRNAs governs BDNF production in the somatal and dendritic compartments to modulate normal and pathological plasticity. This proposal focuses on the following questions: 1) What are the molecular mechanisms and synaptic signals that control BDNF translation in the somatal and dendritic compartments? 2) How are microRNAs involved in translation regulation of BDNF to accommodate neuronal activity changes? 3) What are the functional impacts of activity-dependent BDNF translation in epileptogenesis?

Public Health Relevance

Accurate expression of BDNF is crucial for governing normal neuronal development and function. Either deficiency or exacerbation of BDNF expression can contribute to brain disorders. Thus, understanding the precise regulation of BDNF is a critical prerequisite for developing strategies against many brain diseases. Elucidating molecular mechanisms that underlie BDNF translation in the somatal and dendritic compartments upon neuronal activity changes will provide a conceptual breakthrough for the spatial and temporal control of BDNF-TrkB function. Successful completion of the proposed studies will greatly advance our knowledge regarding how BDNF translation is regulated upon neuronal and synaptic activation, which in turn governs normal as well as pathological plasticity. Moreover, these studies will provide important insights for the fundamental rules that control neuronal activity-dependent translation, especially by microRNA- mediated mechanisms, a timely and important issue in understanding the regulation of many mRNAs in brain neurons, beyond BDNF function.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Neurogenesis and Cell Fate Study Section (NCF)
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Mamounas, Laura
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Emory University
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