Oline K. Rønnekleiv

The Rønnekleiv lab is investigating the function and regulation of gonadotropin releasing hormone (GnRH) neurons. The GnRH neurons control 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 (Rønnekleiv and Resko, Endocrinology, 1990). 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, in combination with a guinea pig 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 which render these neurons responsive to glucose, cell metabolism and estradiol. 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 potassium (Kir) 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. Importantly, both the mRNA expression and function of T-type channels are increased in GnRH neurons by proestrous levels of estradiol.  Additional work focuses on the mechanism by which the neuropeptide kisspeptin regulates GnRH neurons. 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. We have begun to elucidate the underlying ionic mechanisms by which kisspeptin signals in GnRH neurons to activate non-selective cationic (TRPC)-like channels and inhibit Kir channels.

In collaborative projects with the Kelly lab, we are also studying the role of estrogen in modulating hypothalamic control of energy homeostasis. Current studies are focusing on estrogen regulation of proopiomelanocortin (POMC) and neuropeptide Y (NPY) neurons that have opposite roles in the control feeding and metabolism. Other collaborative studies with the Hurn and Alkayed labs include the role of estrogen in neuroprotection following ischemic injury.

KEY PUBLICATIONS

Qiu J, Bosch MA, Tobias SC, Krust A, Graham SM, Murphy SJ, Korach KS, Chambon P, Scanlan TS, Rønnekleiv OK, and Kelly MJ. (2006) A G-protein-coupled estrogen receptor is involved in hypothalamic control of energy homeostasis. J Neurosci. 26: 5649-5655. PMID:16723521.

Qiu J, Bosch MA, Jamali K, Xue C, Kelly MJ, and Rønnekleiv OK. (2006) Estrogen upregulates T-type calcium channels in the hypothalamus and pituitary. J Neurosci. 26: 11072-11082.  PMID:17065449.

Zhang C, Bosch MA, Levine JE, Rønnekleiv OK, and Kelly MJ. (2007) GnRH neurons express K-ATP channels that are regulated by estrogen and responsive to glucose and metabolic inhibition. J Neurosci. 27: 10153-10164. PMID:17881521.

Zhang C, Roepke TA, Kelly MJ, and Rønnekleiv OK. (2008)  Kisspeptin depolarizes gonadotropin-releasing hormone neurons through activation of TRPC-like cationic channels. J. Neurosci. 28: 4423-4434.  PMID:18434521.

Xu C, Roepke TA, Zhang C,  Rønnekleiv OK, and Kelly MJ. (2008) Gonadotropin-releasing hormone (GnRH) activates the m-current in GnRH neurons: an autoregulatory negative feedback mechanism? Endocrinology 149:2459-2466. PMID:18218690.

Bosh MA, Hou J, Fang Y, Kelly MJ,  and Rønnekleiv OK.  (2009) 17Beta-estradiol regulation of the mRNA expression of T-type calcium channel subunits: role of estrogen receptor alpha and estrogen receptor beta.  J Comp Neurol 512:347-358.   PMID:19003958.

Zhang C, Bosch MA, Rick EA, Kelly MJ and Rønnekleiv OK. (2009) 17 Beta-estradiol regulation of T-type calcium channels in gonadotropin-releasing hormone neurons.  J Neurosci 29:10552-10562.  PMID:19710308.