Regulation of BDNF and TrkB Isoforms, their Signaling and Synaptic Modulation

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Brain-derived neurotrophic factor (BDNF) and its receptor (TrkB) play a key role in neuronal and synaptic development and regulation of synaptic connectivity. Changes in BDNF expression or TrkB signalling profoundly impact synaptic development and plasticity. Moreover, deviations from optimal levels of BDNF and TrkB isoforms have severe consequences for brain function, as this can alter synaptic/neuronal function. BDNF is well studied, but less is known about the regulation and biological activity of its isoforms. Similarly, the regulation of TrkB isoforms is not well understood. The long-term goal of my overall research program is to understand how expression and activity of neurotrophins (NGF and BDNF) and their isoforms and receptors are regulated at the transcriptional, post-translational and trafficking levels, to advance our knowledge of basic mechanisms of synapse development, plasticity and function. During the five years of this Discovery Grant, I will study the mechanisms that regulate BDNF and TrkB isoform expression, and how those isoforms impact signaling and synapses. BDNF and TrkB are each found in three isoforms with differing biological activities. Relative levels of these isoforms are regulated post-transcriptionally. However, the mechanisms are unclear. We propose to investigate the role of specific miRNAs and RNA binding proteins in the regulation of the full-length isoform of TrkB (TrkB-FL) and the role of specific proteases in the regulation of BDNF isoforms. Furthermore, we will study the effects of perturbing these regulatory factors on BDNF/TrkB signaling and spine density and morphology in cultured neurons. Lastly, we will study the truncated BDNF isoform, whose receptor binding, signaling and biological activity are uncharacterized. Our Short-Term Objectives are: 1) To explore TrkB-FL regulation by examining TrkB RNA binding factors (protein, miRNA) and their effects on signal transduction and spine measures; 2) To study the regulation of BDNF isoforms by specific proteases and the effects on signal transduction and spine measures; and 3) To determine the biological activity of the truncated BDNF isoform. Significance: My program of research addresses critical gaps in our understanding of BDNF biology. The biosynthesis and function of neurotrophins and how they signal are regulated at many levels, some of which have not been investigated. Understanding the regulation of proteolytic processing of proBDNF, the post-transcriptional regulation of TrkB-FL levels, the biological roles and activities of neurotrophin isoforms, their signalling properties and their effects on neurons and synapses, is critical to our fundamental knowledge of synapse and brain development, regulation and function. The results of this study will lead to new scientific and medical understanding of everyday brain functions such as learning and memory and its dysregulation in psychiatric, neurodevelopmental and neurodegenerative diseases.