My laboratory is interested in elucidating the mechanism by which neurotrophins regulate the formation, maintenance, and function of neural circuits in the brain. Deficiencies in neurotrophins have been linked to neurodegenerative diseases, mental retardation, obesity, and other neurological disorders. Neurotrophins are a family of small and secreted growth factors, which include brain-derived neurotrophic factor (BDNF), nerve growth factor, neurotrophin-3, and neurotrophin-4/5. My laboratory uses a combination of mouse genetic, biochemical, molecular, histological, and behavioral approaches to identify the neural and molecular bases mediating the diverse functions of neurotrophins. We have found that BDNF synthesized in dendrites controls activity-dependent modifications of dendritic spines that are the sites of contact for excitatory synapses. We also found that neurotrophins are required for the formation and maintenance of the striatum. Their deficiencies likely contribute to selective degeneration of striatal neurons in Huntington’s disease. Much of the current work in the laboratory is focused on the regulation of local BDNF synthesis and its role in synaptic plasticity, the molecular mechanism underlying the development and maintenance of the striatum and its relevance to Huntington’s disease, the molecular and neural bases underlying the effect of BDNF on body weight, and the molecular mechanism of retrograde neurotrophic signaling. 

1. Regulation of synaptic plasticity and learning by dendritic local protein synthesis BDNF has been shown to be a powerful regulator of synaptic plasticity.  Our recent findings indicate that dendritically synthesized BDNF plays a vital role in activity-dependent synaptic modifications.  We are interested in how activity controls the transport of mRNAs for BDNF and its receptor TrkB to dendrites and the translation of dendritically localized BDNF and TrkB mRNAs, how locally synthesized BDNF and TrkB proteins are secreted or inserted into the cell membrane in dendrites that contain few Golgi-like organelles, and how locally synthesized BDNF and TrkB regulate synaptic structures.  We also investigate whether down- or up-regulation of local synthesis of BDNF or TrkB affects animal behaviors, including learning and memory, locomotion, eating, and mood.  Since our previous findings show that mice deficient in local BDNF synthesis have spine phenotypes similar to what found in patients with mental retardation, one study is to examine whether deficits in local BDNF synthesis contribute to the pathogenesis of fragile X syndrome, the most common hereditary mental retardation disorder. 

2. Role of neurotrophins in striatal neurons and its relevance to Huntington’s disease The striatum is the largest structure of the basal ganglia and its malfunction has been linked to Parkinson’s disease, Huntington’s disease, schizophrenia, and other neurological disorders. We investigate the role of neurotrophins in the development and survival of striatal neurons and synaptic plasticity at the corticostriatal synapse by selectively deleting the genes for neurotrophins and their receptors in these neurons. Striatal levels of BDNF have been found to be reduced in patients and mice with Huntington’s disease, which is characterized by selective degeneration of one subset of striatal projection neurons. Our recent findings indicate the deficiency in striatal BDNF supply contributes to the pathogenesis of Huntington’s disease. We currently examine whether the BDNF deficiency leads to the selective neurodegeneration in Huntington’s disease. 

3. The neural and molecular mechanisms through which BDNF controls body weight A reduction in expression of either BDNF or TrkB leads to severe obesity in both mice and human. Our previous findings indicate that BDNF synthesized in the ventromedial hypothalamus (VMH) plays a crucial role in the control of body weight. Several ongoing projects aim to link BDNF to the established appetite-controlling pathways, to identify the neural circuit through which BDNF regulates appetite, and to understand how BDNF regulates the function of the circuit. 

4. Role of a novel zinc finger protein in retrograde neurotrophic signaling Many neurons (e.g. motor neurons and sensory neurons) innervate a target far away from their cell bodies. Their development, function, and survival depend on target-derived growth factors. It is an important neurobiology topic to understand how target-derived growth factors retrogradely transmit their signals from axonal terminals to cell bodies over a long distance. We have identified a novel protein that interacts with neurotrophin receptors and is required for retrograde neurotrophic signaling. We employ compartmentalized neuronal cultures and other techniques to elucidate the mechanism by which this novel protein is involved in this retrograde signaling process.

Selected Publications:

•  An, J. J., Gharami, K., Liao, G. Y., Woo, N. H., Lau, A. G., Vanevski, F., Torre, E. R., Jones, K. R., Feng, Y., Lu, B., and Xu, B. 2008. Distinct role of long 3’UTR BDNF mRNA in spine morphology and synaptic plasticity in hippocampal neurons. Cell 134:175-187.

•  Gharami, K., Xie, Y., An, J. J., Tonegawa, S., and Xu, B. 2008. Brain-derived neurotrophic factor over-expression in the forebrain ameliorates Huntington’s disease phenotypes in mice. J. Neurochem. 105:369-379.

•  Xu, B., Goulding, E. H., Zang, K., Cepoi, D., Cone, R. D., Jones, K. R., Tecott, L. H., and Reichardt, L. F. 2003. Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor. Nature Neurosci. 6:736-742.

•  Rico, B., Xu, B., and Reichardt, L. F. 2002. TrkB receptor signaling is required for establishment of GABAergic synapses in the cerebellum. Nature Neurosci. 5:225-233.

•  Xu, B., Zang, K., Ruff, N. L., Zhang, Y. A., McConnell, S. K., Stryker, M. P., and Reichardt, L. F. 2000. Cortical degeneration in the absence of neurotrophin signaling: dendritic retraction and neuronal loss after removal of the receptor TrkB. Neuron 26:233-245.

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