Pregnenolone sulfate enhances neurogenesis and PSA-NCAM in young and aged hippocampus.
Age-dependent cognitive impairments have been correlated with functional and structural modifications in the hippocampal formation. In particular, the brain endogenous steroid pregnenolone-sulfate (Preg-S) is a cognitive enhancer whose hippocampal levels have been linked physiologically to cognitive performance in senescent animals. However, the mechanism of its actions remains unknown. Because neurogenesis is sensitive to hormonal influences, we examined the effect of Preg-S on neurogenesis, a novel form of plasticity, in young and old rats. We demonstrate that in vivo infusion of Preg-S stimulates neurogenesis and the expression of the polysialylated forms of NCAM, PSA-NCAM, in the dentate gyrus of 3- and 20-month-old rats. These influences on hippocampal plasticity are mediated by the modulation of the gamma-aminobutyric acid receptor complex A (GABA(A)) receptors present on hippocampal neuroblasts. In vitro, Preg-S stimulates the division of adult-derived spheres suggesting a direct influence on progenitors. These data provide evidence that neurosteroids represent one of the local secreted signals controlling hippocampal neurogenesis. Thus, therapies which stimulate neurosteroidogenesis could preserve hippocampal plasticity and prevent the appearance of age-related cognitive disturbances.
Mayo
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Laboratoire de Psychobiologie des Comportements Adaptatifs, INSERM U588, Domaine de Carreire, Rue Camille Saint-Saëns, 33077 Bordeaux, France.
Lemaire
V
V
Malaterre
J
J
Rodriguez
J J
JJ
Cayre
M
M
Stewart
M G
MG
Kharouby
M
M
Rougon
G
G
Le Moal
M
M
Piazza
P V
PV
Abrous
D N
DN
D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects*; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D007276:Injections, Intraventricular / Q000379:methods; D008297:Male; D016253:Microscopy, Immunoelectron / Q000379:methods; D039842:Neural Cell Adhesion Molecule L1 / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D011284:Pregnenolone / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism; D012794:Sialic Acids / Q000378:metabolism*; D013997:Time Factors
D039842:Neural Cell Adhesion Molecule L1; D011963:Receptors, GABA-A; D012794:Sialic Acids; C103469:polysialyl neural cell adhesion molecule; C018370:pregnenolone sulfate; D011284:Pregnenolone; D001973:Bromodeoxyuridine