Striatal GDNF Production Is Independent to Circulating Estradiol Level Despite Pan-Neuronal Activation in the Female Mouse

Gender difference in Parkinson’s disease (PD) suggests that female sex steroids may promote dopaminergic neuron survival and protect them from degeneration. The glial cell line-derived neurotrophic factor (GDNF) is believed to be dopaminotrophic; thus it is considered as a potential therapeutic target in PD. Additionally, GDNF is endogenously synthetized in the caudate/putamen of humans and striatum in rodents. A neuroprotective role of estrogens on the nigrostriatal pathway via the stimulation of GDNF has been proposed. Since the GDNF-producing parvalbumin (Parv) interneurons express the estrogen receptor alpha in the mouse striatum, we sought to determine whether ectopic estrogenic compound modulates the GDNF synthesis in mice. Using an ovariectomized-estradiol (E2) replacement regimen, which reliably generates a rise of plasma estradiol, we assessed the effects of different levels of E2 on the activation of striatal neuronal populations, and GDNF production. A strong correlation was found between plasma E2 and the expression of the immediate early gene cFos in the striatum, as well as in other cortical regions. However, moderate and high E2 treatments failed to induce any striatal GDNF mRNA and protein synthesis. High E2 only stimulates cFos induction in a low percentage of striatal Parv neurons whereas the majority of cFos-positive cells are medium spiny neurons. Activation of these projecting neurons by E2 suggests a role of circulating sex steroids in the modulation of striatal neural pathways.This work was supported by: Instituto de Salud Carlos iii, Miguel Servet fellowship CP12-03217 (XDADT), and iPFIS studentship (DEM). Fundación BBVA (XDADT). Fundación Botín (JLB). Centro de Investigación Biomédica en Red, Enfermedades Neurodegenerativas (JLB). Ministerio de Economía y Competitividad: Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016 (JLB).Peer reviewe