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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
7P01HD023315-26
Application #
8733295
Study Section
Special Emphasis Panel (ZHD1-MCHG-B (DC))
Project Start
2013-07-03
Project End
2014-06-30
Budget Start
2013-07-03
Budget End
2014-06-30
Support Year
26
Fiscal Year
2013
Total Cost
$181,525
Indirect Cost
$25,722
Name
Rbhs-Robert Wood Johnson Medical School
Department
Type
DUNS #
078795875
City
Piscataway
State
NJ
Country
United States
Zip Code
08854
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Mony, Tamanna Jahan; Lee, Jae Won; Dreyfus, Cheryl et al. (2016) Valproic Acid Exposure during Early Postnatal Gliogenesis Leads to Autistic-like Behaviors in Rats. Clin Psychopharmacol Neurosci 14:338-344
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Ma, Qian; Yang, Jianmin; Li, Thomas et al. (2015) Selective reduction of striatal mature BDNF without induction of proBDNF in the zQ175 mouse model of Huntington's disease. Neurobiol Dis 82:466-77
Anastasia, Agustin; Barker, Phillip A; Chao, Moses V et al. (2015) Detection of p75NTR Trimers: Implications for Receptor Stoichiometry and Activation. J Neurosci 35:11911-20
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

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