Understanding how a neural circuitry is modified from experience or in disease requires a fundamental understanding of how presynaptic changes in transmitter release coordinate with postsynaptic changes in response. I study a model of neuronal adaptation to chronic inactivity in which the postsynaptic expression of surface GluR1-containing 1-amino-3-hydroxyl-5-methyl-4- isoxazole-propionate (AMPA) receptors is increased during the inactivity while the rate of presynaptic release increases after inactivity relief. In addition, this increase in presynaptic release requires flux through the postsynaptic GluR1-containing AMPA receptors and the signaling of brain-derived neurotrophic factor (BDNF). These observations suggest the existence of a post-to-pre trans-synaptic coordination in which GluR1-containing AMPA receptors may initiate the postsynaptic events and BDNF may as a retrograde messenger to regulate presynaptic function. However, the roles of GluR1 and BDNF in this trans-synaptic coordination are incompletely understood and their relationship is unclear. To address these gaps in understanding, I will use biochemical, genetic, electrophysiological and optical methods to determine 1) how GluR1-containing AMPA receptors selectively accumulate at the postsynapse, 2) whether BDNF is a retrograde messenger, and 3) how GluR1-containing receptors regulate BDNF signaling. Elucidating the roles of GluR1 and BDNF in trans-synaptic coordination will advance our fundamental understanding of plasticity mechanisms and is likely to provide insights into diseases in which synaptic function is defective such as in Alzheimer's disease and in epilepsy.
My research in understanding the molecular mechanisms underlying connective changes in neural circuitry can lead to new insights into mental disorders, one of the leading causes of disability in the United States. Moreover, these insights can provide new therapeutic targets, open new avenues of treatments, and pave the road to potential cures for these disorders. Thus, the long-term goal of this research is to improve public health with discoveries that can improve mental health.
|Yoo, Andrew S; Sun, Alfred X; Li, Li et al. (2011) MicroRNA-mediated conversion of human fibroblasts to neurons. Nature 476:228-31|