The Program Project hypothesizes that the processes of progenitor proliferation, neural differentiation, axon extension and synapse formation are regulated by neuron-neuron and neuron-glial interactions. These cell-cell interactions, in turn, are mediated through the actions of multiple intercellular and intracellular signals that impact seemingly unrelated developmental events. Our studies will elucidate molecules and mechanisms that regulate proliferation, survival, differentiation and synaptogenesis in the developing brain. They focus on the roles of BDNF and Eph family members and lead us to increased understanding of how to effect brain repair and regeneration. Importantly, the studies move from the culture dish, to the developing brain in vivo. Moreover, they extend the work to analysis of a neurotherapeutic molecule used for women of childbearing age. To achieve our goals. Project 1 will examine mechanisms by which the anticonvulsant, valproic acid affects development of neurons and glia, ranging from proliferation control to differentiation, neurotrophin signaling and behavioral consequences. Project 2 will explore an emerging field of signal interaction between Eph and Trk family receptors. Project 3 will define mechanisms underlying synaptic plasticity by examining the roles of cytoskeletal structures in transmitter receptor trafficking and spine enlargement/formation and shrinkage and their regulation by intracellular kinases and BDNF. Project 4 will explore mechanisms underlying the processing and release of pro- and mature isoforms of BDNF from neurons. Project 5 will examine roles played by astrocytes in providing BDNF to effect development and maintenance of proximate neurons and oligodendrocytes.
This program explore mechanisms impacting BDNF release and the building of neuronal connections. Moreover, it examines effects of a neurotherapeutic, valproic acid, given to women of childbearing age. Disregulation of these processes is a significant component of neurodevelopmental pathologies. Further, abnormal fronto-limbic connectivity underlies conditions such as anxiety and autism. The mechanisms established in this program are likely to yield new targets for examination in these developmental 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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