Brain derived neurotrophic factor (BDNF), a member of the neurotrophin family, plays fundamental roles in neuronal survival, differentiation, circuitr formation/reconstruction, and synaptic plasticity. Deficiency in BDNF functions has been implicated in psychiatric disorders, depression, and learning-memory deficits. BDNF actions on neuronal circuitry are circuitry- and synapse-selective actions, implicating a potential involvement of localized expression/release of BDNF proteins. The primary BDNF transcript is processed at two alternative polyadenylation sites, giving rise to two pools of BDNF mRNAs harboring a short and a long 3'UTR of 0.35 kb and 2.85 kb but encoding the same BDNF protein. The long 3'UTR contains additional distinct sequence entities, which offer specific posttranscriptional regulation of BDNF. BDNF mRNA bearing the short 3'UTR is restricted in the cell body whereas that bearing long 3'UTR is present in the dendritic region. Importantly, the long 3'UTR is responsible for dendritic targeting of BDNF mRNA, which is enhanced by neuronal activity. Furthermore, the long 3'UTR was found to repress BDNF translation in resting neurons but undergoes activity-dependent BDNF translation in dendrites. Loss of the BDNF long 3'UTR results in defects in dendritic spine development and plasticity, indicating an important role for dendritic expression of BDNF through the long transcripts. We hypothesize that the long 3'UTR BDNF mRNA may mediate translation of BDNF in selective dendritic regions in response to local synaptic activities, leading to spatiotemporally restricted BDNF release for synapse-specific modification of synapses. This proposed study will evaluate this exciting hypothesis and address several crucial issues concerning BDNF generated from the long 3'UTR transcripts. Of most importance is whether BDNF protein is locally produced from long 3'UTR transcripts by synaptic activity, packed into vesicles, and released from stimulated synapses. It is also important to know if BDNF proteins translated from the short and long transcripts behave differentially in terms of their distribution, trafficking, and release in respose to local synaptic activity. Advanced live cell imaging will be performed to address three specific questions: (1) whether the long 3'UTR BDNF transcripts mediate activity-dependent localized translation of BDNF;(2) whether BDNF proteins synthesized from the long 3'UTR transcripts are packed in vesicles, and can localize to the site of synaptic activities;(3) whether BDNF proteins synthesized from the long 3'UTR transcripts can actually be released in response to synaptic activities. Answers to these questions will provide the support to a novel mechanism concerning BDNF production, trafficking, and secretion that may play an important role in synaptic modifications. Results from this study could have a major impact on our understanding of the molecular and cellular mechanisms underlying BDNF functions in normal and disease brains.

Public Health Relevance

Brain derived neurotrophic factor (BDNF) plays a crucial role in brain development and functions but is produced from two pools of BDNF mRNAs harboring a short and a long 3'UTR. This study will evaluate if the long 3'UTR BDNF mRNA mediate local translation and release of BDNF for synaptic modification. Results from this study could have a major impact on our understanding of BDNF functions in normal and disease brains, thus having direct relevance to public health.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Exploratory/Developmental Grants (R21)
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Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
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Asanuma, Chiiko
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Emory University
Schools of Medicine
United States
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