Diazepam binding inhibitor promotes progenitor proliferation in the postnatal SVZ by reducing GABA signaling

TY - JOUR

T1 - Diazepam binding inhibitor promotes progenitor proliferation in the postnatal SVZ by reducing GABA signaling

AU - Alfonso, Julieta

AU - Le Magueresse, Corentin

AU - Zuccotti, Annalisa

AU - Khodosevich, Konstantin

AU - Monyer, Hannah

N1 - Copyright © 2012 Elsevier Inc. All rights reserved.

PY - 2012/1/6

Y1 - 2012/1/6

N2 - The subventricular zone (SVZ) of the lateral ventricles is the largest neurogenic niche of the postnatal brain. New SVZ-generated neurons migrate via the rostral migratory stream to the olfactory bulb (OB) where they functionally integrate into preexisting neuronal circuits. Nonsynaptic GABA signaling was previously shown to inhibit SVZ-derived neurogenesis. Here we identify the endogenous protein diazepam binding inhibitor (DBI) as a positive modulator of SVZ postnatal neurogenesis by regulating GABA activity in transit-amplifying cells. We performed DBI loss- and gain-of-function experiments in vivo at the peak of postnatal OB neuron generation in mice and demonstrate that DBI enhances proliferation by preventing SVZ progenitors to exit the cell cycle. Furthermore, we provide evidence that DBI exerts its effect on SVZ progenitors via its octadecaneuropeptide proteolytic product (ODN) by inhibiting GABA-induced currents. Together our data reveal a regulatory mechanism by which DBI counteracts the inhibitory effect of nonsynaptic GABA signaling on subventricular neuronal proliferation.

AB - The subventricular zone (SVZ) of the lateral ventricles is the largest neurogenic niche of the postnatal brain. New SVZ-generated neurons migrate via the rostral migratory stream to the olfactory bulb (OB) where they functionally integrate into preexisting neuronal circuits. Nonsynaptic GABA signaling was previously shown to inhibit SVZ-derived neurogenesis. Here we identify the endogenous protein diazepam binding inhibitor (DBI) as a positive modulator of SVZ postnatal neurogenesis by regulating GABA activity in transit-amplifying cells. We performed DBI loss- and gain-of-function experiments in vivo at the peak of postnatal OB neuron generation in mice and demonstrate that DBI enhances proliferation by preventing SVZ progenitors to exit the cell cycle. Furthermore, we provide evidence that DBI exerts its effect on SVZ progenitors via its octadecaneuropeptide proteolytic product (ODN) by inhibiting GABA-induced currents. Together our data reveal a regulatory mechanism by which DBI counteracts the inhibitory effect of nonsynaptic GABA signaling on subventricular neuronal proliferation.

KW - Animals

KW - Cell Cycle/physiology

KW - Diazepam Binding Inhibitor/metabolism

KW - GABAergic Neurons/cytology

KW - Mice

KW - Mice, Transgenic

KW - Neuropeptides/metabolism

KW - Olfactory Bulb/cytology

KW - Peptide Fragments/metabolism

KW - Signal Transduction/physiology

KW - Stem Cells/cytology

KW - gamma-Aminobutyric Acid/genetics

U2 - 10.1016/j.stem.2011.11.011

DO - 10.1016/j.stem.2011.11.011

M3 - Journal article

C2 - 22226357

SN - 1934-5909

VL - 10

SP - 76

EP - 87

JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 1

ER -