The postnatal subventricular zone (SVZ) is a germinal center composed of a network of chains of migrating and proliferative neuroblasts ensheathed by glial fibrillary acidic protein immunopositive (GFAP+) cells, which display the characteristics of stem cells. The progenitors migrate throughout the SVZ and along the rostral migratory stream (RMS) toward the olfactory bulb where they continuously replace interneurons throughout life. Identifying the signals influencing the behavior of SVZ progenitors would lead to a better basic understanding of the mechanisms influencing replacement of olfactory bulb interneurons, and is necessary to design strategies to promote neurogenesis and self-repair. The production of progenitors is thought to be regulated by molecules providing communication signals between neuroblasts and GFAP+ cells, yet our knowledge of such signaling remains rudimentary. The central hypothesis of this grant is that glutamatergic signaling from GFAP+ cells to neuroblasts balances GABA's inhibitory function by promoting the proliferation of postnatal SVZ progenitors.
Three aims will be addressed. First we will determine whether a fast glutamatergic signaling from GFAP+ cells to neuroblast exists. As neuroblasts signal to GFAP+ cells via GABAergic signaling, glutamatergic signaling would provide a feedback loop necessary for a bidirectional communication between these two cell types. Second, we will determine whether PGE2 released from SVZ cells modulates glutamate release from GFAP+ cells and thus mGluR activation. Finally, we will determine whether glutamate and PGE2's modulation of glutamate release provide a positive control on cell proliferation to counterbalance GABA's inhibitory influence. We will use patch-clamp and Ca2+ imaging techniques, and perform proliferation assays in brain slices and in vivo. We will use CD1 mice and several lines of transgenic mice to address our aims. It is hoped that together the proposed experiments will identify the existence and function of a bidirectional communication between GFAP+ cells and neuroblasts, and further our understanding of how intercellular signaling regulates postnatal neurogenesis. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC007681-02
Application #
7409708
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Davis, Barry
Project Start
2007-04-20
Project End
2012-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
2
Fiscal Year
2008
Total Cost
$408,424
Indirect Cost
Name
Yale University
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Platel, J C; Bordey, A (2016) The multifaceted subventricular zone astrocyte: From a metabolic and pro-neurogenic role to acting as a neural stem cell. Neuroscience 323:20-8
Lafourcade, Carlos A; Lin, Tiffany V; Feliciano, David M et al. (2013) Rheb activation in subventricular zone progenitors leads to heterotopia, ectopic neuronal differentiation, and rapamycin-sensitive olfactory micronodules and dendrite hypertrophy of newborn neurons. J Neurosci 33:2419-31
Feliciano, David M; Bordey, Angélique (2013) Newborn cortical neurons: only for neonates? Trends Neurosci 36:51-61
Pathania, Manavendra; Torres-Reveron, Juan; Yan, Lily et al. (2012) miR-132 enhances dendritic morphogenesis, spine density, synaptic integration, and survival of newborn olfactory bulb neurons. PLoS One 7:e38174
Lacar, Benjamin; Herman, Peter; Hartman, Nathaniel W et al. (2012) S phase entry of neural progenitor cells correlates with increased blood flow in the young subventricular zone. PLoS One 7:e31960
Lacar, Benjamin; Herman, Peter; Platel, Jean-Claude et al. (2012) Neural progenitor cells regulate capillary blood flow in the postnatal subventricular zone. J Neurosci 32:16435-48
Lacar, Benjamin; Young, Stephanie Z; Platel, Jean-Claude et al. (2012) Preparation of acute subventricular zone slices for calcium imaging. J Vis Exp :e4071
Young, Stephanie Z; Taylor, M Morgan; Wu, Sharon et al. (2012) NKCC1 knockdown decreases neuron production through GABA(A)-regulated neural progenitor proliferation and delays dendrite development. J Neurosci 32:13630-8
Lacar, Benjamin; Young, Stephanie Z; Platel, Jean-Claude et al. (2011) Gap junction-mediated calcium waves define communication networks among murine postnatal neural progenitor cells. Eur J Neurosci 34:1895-905
Young, Stephanie Z; Taylor, M Morgan; Bordey, Angelique (2011) Neurotransmitters couple brain activity to subventricular zone neurogenesis. Eur J Neurosci 33:1123-32

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