Abstract
BackgroundNeurogenesis in the hippocampal dentate gyrus and the subventricular zone occurs throughout the life of mammals and newly generated neurons can integrate functionally into established neuronal circuits. Neurogenesis levels in the dentate gyrus are modulated by changes in the environment (enrichment, exercise), hippocampal-dependent tasks, NMDA receptor (NMDAR) activity, sonic hedgehog (SHH) and/or other factors.Resultspreviously, we showed that Protease Nexin-1 (PN-1), a potent serine protease inhibitor, regulates the NMDAR availability and activity as well as SHH signaling. Compared with wild-type (WT), we detected a significant increase in BrdU-labeled cells in the dentate gyrus of mice lacking PN-1 (PN-1 -/-) both in controls and after running exercise. Patched homologue 1 (Ptc1) and Gli1 mRNA levels were higher and Gli3 down-regulated in mutant mice under standard conditions and to a lesser extent after running exercise. However, the number of surviving BrdU-positive cells did not differ between WT and PN-1 -/- animals. NMDAR availability was altered in the hippocampus of mutant animals after exercise.ConclusionAll together our results indicate that PN-1 controls progenitors proliferation through an effect on the SHH pathway and suggest an influence of the serpin on the survival of newly generated neurons through modulation of NMDAR availability.
Highlights
Neurogenesis in the hippocampal dentate gyrus and the subventricular zone occurs throughout the life of mammals and newly generated neurons can integrate functionally into established neuronal circuits
All together our results indicate that Protease Nexin-1 (PN-1) controls progenitors proliferation through an effect on the sonic hedgehog (SHH) pathway and suggest an influence of the serpin on the survival of newly generated neurons through modulation of NMDA receptor (NMDAR) availability
PN-1 expression in the dentate gyrus Using PN-1 knock-in reporter mice (PN-1 KI) [29], we first analyzed PN-1 expression by monitoring X-Gal staining in the brain following running wheel exercise (Fig. 1)
Summary
Neurogenesis in the hippocampal dentate gyrus and the subventricular zone occurs throughout the life of mammals and newly generated neurons can integrate functionally into established neuronal circuits. Granule neurons are generated from a population of continuously dividing cells residing in the subgranular zone of the dentate gyrus [2,5,6]. These "newborn" progenitor cells migrate into the granule cell layer, differentiate, extend axons and express neuronal marker proteins [7].
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