Estrogen Receptor Alpha in the Brain (POA)
The Ronnekleiv lab is investigating the function and regulation of gonadotropin releasing hormone (GnRH) neurons. The GnRH neurons controls reproduction and are therefore critical for the survival of the species. These neurons migrate from the nose during development to their species-specific location in the hypothalamus. The neurons are scattered in the hypothalamus and have, therefore, been difficult to study. A great step forward was the production of transgenic mice that express green fluorescence protein attached to the GnRH promoter. This makes GnRH neurons fluorescence so that they can be visualized for experimentation purposes.
Our current work uses this transgenic mouse model to study the mechanism by which estrogen, neurotransmitters and metabolic factors regulate GnRH neurons. For our studies we are combining whole cell patch recording with molecular biology to explore membrane properties, intracellular signaling and gene expression in individual GnRH neurons. We have recently discovered that GnRH neurons express K-ATP channels and glucokinase, similar to pancreatic beta cells, which render these neurons responsive to glucose, cell metabolism and estrogen. Therefore, GnRH neurons have the ability to integrate metabolic changes, hormonal fluctuations and sensory input all important for the control of reproduction. The discovery of this inwardly rectifying channel in GnRH neurons fits into our working model of the conductances that contribute to burst firing in these neurosecretory neurons. Indeed, we have also discovered a pacemaker channel (h-channel) and the T-type calcium channel in these neurons.
Our current work focuses on the mechanism by which kisspeptin, a GnRH releasing factor, induces burst firing and GnRH release. To date, kisspeptin neurons provide the most potent excitatory drive to GnRH neurons and it is known that patients with deletion in its cognate receptor (GPR 54) exhibit hypothalamic hypogonadism(see also Herbison lab paper and GPR54 clinical papers: de Roux et al. and Seminara et al.