Resumen de The role of GnRH in the age-related cognitive decline in some disorders including Down syndrome
The role of gonadotropin-releasing hormone (GnRH) neurons as the master regulators of acomplex neural network, mainly in the hypothalamus, controlling the onset of puberty andregulation of fertility is well established. Nonetheless, it is becoming apparent that GnRH maybe involved in a variety of non-reproductive functions. Here, we show that GnRH neurons arecritical for maintaining cognitive function and olfaction. A first study demonstrates adysregulated microRNA (miR)-transcription network underlying a progressive loss of GnRHexpression in the Ts65Dn mice, a mouse model of Down syndrome. This GnRH loss isconcomitant with a cognitive and olfactory decline. Intriguingly, these deficits are reversibleby viral-vector-mediated miR-200b overexpression, the restoration of GnRH functionality bygrafting wild-type GnRH neurons, or simply delivering pulsatile GnRH. A second studydemonstrates mutations in the neuronal nitric oxide (NO) synthase (NOS1) gene as a causalfactor of congenital hypogonadotropic hypogonadism and Kallmann syndrome, two geneticdisorders rooted in a GnRH deficiency. Similar to human, Nos1 deficient mice do not only showa delayed puberty onset and infertility, but also cognitive and olfactory impairments.Moreover, the administration of inhaled NO during the late infantile period can restore sexualmaturation, cognition and olfaction in this mouse model. Overall, the results of this Ph.D.thesis provide evidence that GnRH plays an unexpected yet critical role in non-reproductivefunctions such as cognitive function and olfaction and hold novel opportunities for therapeuticstrategies against various neurodevelopmental and neurodegenerative disorders.
