It is now clear that astrocytes (asts) have varied and critical functions that may impact the developing and mature brain. For example, culture and slice preparations of asts indicate that ast-derived molecules participate in the survival and differentiation of neurons as well as their synaptic function [1-3]. Moreover, ast-derived molecules may affect proliferation and differentiation of oligodendrocyte (olg) lineage cells [4-6]. The regulatory events that controlthese ast-associated processes are being understood. In particular, asts respond to neurotransmitters with increases in Ca+2 that can be propagated to adjacent asts in the form of Ca+2 waves [7, 8]. Further they release neuroactive substances such as glutamate, L-serine, D-serine and ATP that impact neuron function [9-12]. During the last grant period we found that cultured asts, through a similar mechanism, may impact neurons through synthesis and release of brain-derived neurotrophic factor (BDNF), a molecule known to impact neuronal survival, differentiation and synapse formation as well as olg proliferation and differentiation in selective brain regions. We therefore hypothesize that asts, through their production and release of BDNF play an active and critical role in the differentiation and perhaps maintenance of proximate neural cells during development. To explore the in vivo importance of asts and further define mechanisms underlying the role of asts as BDNF providers:
Aim 1 will use HA-BDNF mice (being analyzed by Hempstead) to examine development of BDNF+ asts during the postnatal period in the BF and determine a) when BDNF is present in vesicles and available to impact neurons and oigs during development, b) how the presence of BDNF in vesicles changes during development and c) the source of ast BDNF, whether endogenous or exogenous.
Aim 2 will use conditional knockout mice that delete astderived BDNF upon tamoxifen injection to define effects of ast-derived BDNF on cholinergic neurons and oIgs during postnatal development of the BF in vivo.
Aim 3 will identify the transport processes that are responsible for regulated release of newly synthesized and endocytosed BDNF and molecular events that impact this process.

Public Health Relevance

; These studies will examine the role of ast-derived BDNF on neuron and olg development and define underlying mechanisms. It places us in position to dissect and manipulate molecular events regulating BDNF release from asts that occur during development and in response to metabotropic stimulation. Moreover, they identify therapeutic targets that may be impacted by drugs, such as the anticonvulsant valproic acid taken by women of childbearing age.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Program Projects (P01)
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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
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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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