Home > Funded Projects > Hypocretin/orexin deficiency in Prader-Willi syndrome animal models

The Prader-Willi syndrome (PWS) is a disease caused by mutations on human chromosome 15 leading to “floppy” infants initially, and obesity and sleep disorders later. Although genetic defects underlying PWS have been documented, it is still not well understood how the loss-of-function of genes results in various symptoms in PWS. It has been shown that the dysfunction of the hypothalamus, a brain structure, contributes to symptoms seen in PWS patients. Since the hypothalamus comprises many specific types of nerve cells (neurons) with distinct functions, it is essential to pinpoint changes in these neurons responsible for PWS. Recent progress in clinical research has suggested that impaired function of a specific group of neurons that synthesize the neuropeptide hypocretin (also called orexin)in the lateral hypothalamus, may be responsible for sleep problems and excessive daytime sleepiness in PWS. Hypocretin/orexin promotes wakefulness in humans and animals. A dysfunctional hypocretin/orexin system has been found in diseases and conditions that exhibit abnormal sleep patterns as seen in PWS. In this application, we will examine the hypothesis that dysfunction of hypocretin/orexin neurons is responsible for sleep disturbances in PWS. Since PWS is a complicated disease involving defects in many genes, it is essential to delineate the contribution of each defective gene to PWS symptoms. Animal models involving mutations of individual genes have provided additional insight into our understanding of PWS. By using a sophisticated approach to directly monitor activities in hypocretin/orexin neurons in live brain tissues from normal and PWS-like mice, we will study two factors determining the function of these neurons. First, we will discern the capability of hypocretin/orexin neurons to generate nerve impulses (action potentials), which triggers the release of hypocretin/orexin. Next, we will examine stimulatory inputs onto hypocretin/orexin neurons, which promote the induction of action potentials. We expect that these two functions would be compromised in PWS mice with sleep disturbances, helping to explain the lowered levels of hypocretin/orexin in PWS patients. We hope that our results will start a new avenue to understand the connections between genetic causes and diagnosed symptoms, and ultimately lead to the development of new treatments for PWS.

In our study, we demonstrated an impaired synaptic transmission onto hypocretin neurons in addition to the reduced number of hypocretin cells in Magel2 KO mice, which may explain the impaired sleep/wake phenotype reported in these animals by Kozlov and colleagues. These results may also provide critical insights into the excessive daytime sleepiness (EDS) in PWS patients, since no loss of Hcrt cells is found in PWS patients. It is also important to notice the possible compensation in the intrinsic excitability in Hcrt neurons in Magel2 KO mice, which may suggest the self-repair in the Hcrt system in these animals and possibly in PWS patients.

Other Outcomes:
Gan, G., Weng, Y., Suyama, S. and Gao, XB. Hypocretin/orexin neurons in a Prader-Willi syndrome animal model. Program # 505.17. 2011 Neuroscience Meeting Planner. Washington, DC: Society for Neuroscience, 2011. Online.

Funded Year:


Awarded to:

Xiao-Bing Gao, Ph.D.




Yale University