Role of neurosteroids, steroid receptors and the gabaergic pathway on exacerbated neurogenesis of the GABA B receptor KO mouse

GARAY L; DI GIORGIO N; GONZALEZ- GIQUEAUX P; GONZALEZ DENISELLE, MC; LIMA ANALÍA; BETTLER BERNHARD; LUX-LANTOS V; DE NICOLA A. F.

Congreso; LXI Reunión Anual de la Sociedad Argentina de Investigación Clínica (SAIC).; 2016

Adult neurogenesis is tightly regulated through the interaction of neural progenitor cells with diverse signal in the niche derived by neurotrophins, neurotransmitters, steroids among other factors. GABA signaling through GABA A receptors regulates the entire process of neurogenesis while the effects through the metabotropic GABA B receptors were less studied conferring an inhibitor role. In this work we analyzed the influence of GABA and the steroidogenic pathway on the exacerbated neurogenesis observed in the GABA B KO mice (GABA KO). GABA KO showed a 2.2 fold increase in the number of doublecortin (DCX) positive cells accompanied by an enlargement of the dentate gyrus blades width stained with cresyl violet compared to WT mice. Aberrant expression of young neurons may contribute to network hyperexcitability since a higher expression of early genes c-fos and c-jun were observed in CA1, CA3 and the hilus of the hippocampus. Lack of GABA B receptor increased 1.5 fold the number of GABA+ interneurons in the stratum lacunosum moleculare, and the number of GFAP + astrocytes and Glutamine sintetase (GS) + cells in diverse areas of the hippocampus. In order to evaluate if steroids were also affected in GABA B KO, the steroidogenic pathway was assessed. The expression of steroidogenic proteins (STAR, PBR), enzymes (3βHSD,5α-Reductase, Aromatase) and steroids receptors (AR, ER,MR) were not modified in GABA KO compared to WT mice. Furthermore, to analyze if estrogens were involved in the increased neurogenesis and gliosis in this model, an aromatase inhibitor (anastrazole) was administered daily (1mg/Kg) for fifteen days i.p. No changes were observed in DCX, GFAP or GS hyperexpression. In conclusion, GABAergic but not estrogenic pathway is altered in GABA B KO aberrant neurogenesis. These results may contribute to understand molecular mechanisms associated to aberrant neurogenesis in human diseases such as epilepsy.