Adult Hippocampal Neurogenesis Modulation by the Membrane-Associated Progesterone Receptor Family Member Neudesin

Abstract

Neudesin (Neuron-derived neurotrophic factor, NENF), a membrane-associated progesterone receptor family (MAPR) member, is a neuron secreted protein with neurotrophic properties during embryonic stages. However, its role in the adult brain is still poorly addressed. In this study we have used neudesin-null (Nenf^-/-) mice and performed a characterization of the proliferation state of the adult neurogenic niches, the adult subventricular zone (SVZ) and the hippocampus subgranular zone (SGZ). Nenf^-/- males did not presented any deficits in proliferation in the SVZ neither <i>in vivo</i> nor <i>in vitro</i>. On the other hand a decrease in cell proliferation in the SGZ was observed, as well as a decrease in the number of newborn neurons in the dentate gyrus (DG) that was accompanied by impaired context discrimination in a contextual fear conditioning (CFC) task. Since NENF neurotrophic action is suggested to occur via the formation of a progesterone stability complex for the activation of non-genomic cascade, we further evaluated progesterone metabolism in the absence of NENF. Interestingly, expression of progesterone catabolic rate-determining enzyme, 5-α-reductase was upregulated in the DG of Nenf^-/-, together with a significant increase in the expression of the δGABA_A receptor gene, involved in DG tonic inhibition. Taken together, these findings add <i>in vivo</i> evidence on the neurotrophic properties of NENF in the adult brain. Furthermore, the mechanism of action of NENF in this process might implicate neurosteroids modulation, at least in the DG.