BDNF induces structural and functional changes in central neurons to modulate synaptic efficacy;our goal is to identify molecular mechanisms that regulate BDNF targeting and release at synapses to modulate neurotransmission. BDNF is synthesized as a precursor, proBDNF, sorted to a regulated secretory pathway, and released in an activity-dependent manner. At the synapse, proBDNF can bind selectively to p75 to induce LTD, and potentially reduce spine density and dendritic complexity. If proBDNF is converted to mature BDNF in the secretory vesicle or synaptic cleft, TrkB is selectively activated to enhance synaptic transmission and promote axonal branching and dendritic growth. Thus, mechanisms that regulate conversion of proBDNF to mature BDNF, and regulate trafficking to dendrites or axons critically modulate structural and functional neuronal plasticity. We have generated knock-in mice expressing HA-tagged BDNF to markedly enhance detection of endogenous BDNF. We have also identified intracellular chaperones, including sortilin, and other sortilin family members that bind proBDNF. With these tools, three interrelated aims are proposed: (1) Using neurons from the BDNF-HA mouse, identify if conversion of proBDNF to mature BDNF occurs during sorting to secretory vesicles, or following vesicle fusion and release. We postulate that the location of BDNF conversion may differ among neuronal subtypes. (2) We will identify the sortilin family members that chaperone proBDNF to the constitutive or regulated secretory pathways, and to dendrites or axons. We posit that different sortilin members direct intracellular trafficking to different subcellular compartments, delivery to the synapse, and regulate cleavage to mature BNDF. Using BDNF-HA mouse, and acute silencing of different chaperones, we will assess the developmentally regulated changes in the ratio of proBDNF/mature BDNF release, and in retrograde and anterograde traffiking of BDNF isoforms. (3) We will generate knock-in mice to conditionally delete relevant sortilin family members. These animals will permit us to dissect the roles of select BDNF chaperones in regulating BDNF levels, targeting to axons or dendrites, and effects on neuronal morphology and connectively in the intact, postnatal brain.
This project identifies mechanisms that regulate BDNF release, and modulates morphology and connectivity of hippocampal and cortical neurons;disregulation of these processes contributes to neurodevelopmental disease. A human SNP that reduces BDNF release results in anxiety and depressive symptoms in mice, and correlates with these human diseases. Abnormal frontolimbic connectivity underlies conditions of anxiety and autism. The mechanisms identified here will yield new targets for examination in these diseases.
|Deinhardt, Katrin; Chao, Moses V (2014) Shaping neurons: Long and short range effects of mature and proBDNF signalling upon neuronal structure. Neuropharmacology 76 Pt C:603-9|
|Yang, Jianmin; Harte-Hargrove, Lauren C; Siao, Chia-Jen et al. (2014) proBDNF negatively regulates neuronal remodeling, synaptic transmission, and synaptic plasticity in hippocampus. Cell Rep 7:796-806|
|Fulmer, Clifton G; VonDran, Melissa W; Stillman, Althea A et al. (2014) Astrocyte-derived BDNF supports myelin protein synthesis after cuprizone-induced demyelination. J Neurosci 34:8186-96|
|Bowling, Heather; Zhang, Guoan; Bhattacharya, Aditi et al. (2014) Antipsychotics activate mTORC1-dependent translation to enhance neuronal morphological complexity. Sci Signal 7:ra4|
|Sheleg, Michal; Yochum, Carrie L; Wagner, George C et al. (2013) Ephrin-A5 deficiency alters sensorimotor and monoaminergic development. Behav Brain Res 236:139-47|
|Das, Gitanjali; Reuhl, Kenneth; Zhou, Renping (2013) The Golgi-Cox method. Methods Mol Biol 1018:313-21|
|Anastasia, Agustin; Deinhardt, Katrin; Chao, Moses V et al. (2013) Val66Met polymorphism of BDNF alters prodomain structure to induce neuronal growth cone retraction. Nat Commun 4:2490|
|Lee, Chi Wai; Vitriol, Eric A; Shim, Sangwoo et al. (2013) Dynamic localization of G-actin during membrane protrusion in neuronal motility. Curr Biol 23:1046-56|
|Huang, Yangyang; Dreyfus, Cheryl F (2013) Culturing astrocytes from postnatal rats. Methods Mol Biol 1018:71-80|
|Rui, Yanfang; Myers, Kenneth R; Yu, Kuai et al. (2013) Activity-dependent regulation of dendritic growth and maintenance by glycogen synthase kinase 3*. Nat Commun 4:2628|
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