The development of hypocretin (orexin) deficiency in hypocretin/ataxin-3 transgenic rats.

Abstract

Narcolepsy is linked to a widespread loss of neurons containing the neuropeptide hypocretin (HCRT), also named orexin. A transgenic (TG) rat model has been developed to mimic the neuronal loss found in narcoleptic humans. In these rats, HCRT neurons gradually die as a result of the expression of a poly-glutamine repeat under the control of the HCRT promoter. To better characterize the changes in HCRT-1 levels in response to the gradual HCRT neuronal loss cerebrospinal fluid (CSF) HCRT-1 levels were measured in various age groups (2-82 weeks) of wild-type (WT) and TG Sprague-Dawley rats. TG rats showed a sharp decline in CSF HCRT-1 level at week 4 with levels remaining consistently low (26%+/-9%, mean+/-S.D.) thereafter compared with WT rats. In TG rats, HCRT-1 levels were dramatically lower in target regions such as the cortex and brainstem (100-fold), indicating decreased HCRT-1 levels at terminals. In TG rats, CSF HCRT-1 levels significantly increased in response to 6 h of prolonged waking, indicating that the remaining HCRT neurons can be stimulated to release more neuropeptide. Rapid eye movement (REM) sleep in TG rats (n=5) was consistent with a HCRT deficiency. In TG rats HCRT immunoreactive (HCRT-ir) neurons were present in the lateral hypothalamus (LH), even in old rats (24 months) but some HCRT-ir somata were in various stages of disintegration. The low output of these neurons is consistent with a widespread dysfunction of these neurons, and establishes this model as a tool to investigate the consequences of partial hypocretin deficiency.

• Authors: S Zhang, L Lin, S Kaur, S Thankachan, C Blanco-Centurion, M Yanagisawa, E Mignot, P J Shiromani
• Journal: Neuroscience (Neuroscience) Vol. 148 Issue 1 Pg. 34-43 (Aug 10 2007) ISSN: 0306-4522 [Print] United States
• PMID: 17618058 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S., Validation Study)

Chemical References

• Intracellular Signaling Peptides and Proteins
• Nerve Tissue Proteins
• Neuropeptides
• Nuclear Proteins
• Orexins
• Peptides
• Repressor Proteins
• polyglutamine
• ATXN3 protein, human
• Ataxin-3

Topics

• Aging (metabolism)
• Animals
• Animals, Genetically Modified
• Ataxin-3
• Disease Models, Animal
• Female
• Hypothalamus (metabolism, physiopathology)
• Immunohistochemistry
• Intracellular Signaling Peptides and Proteins (cerebrospinal fluid, genetics)
• Male
• Narcolepsy (cerebrospinal fluid, genetics, physiopathology)
• Nerve Degeneration (cerebrospinal fluid, genetics, physiopathology)
• Nerve Tissue Proteins (genetics)
• Neurons (metabolism)
• Neuropeptides (cerebrospinal fluid, genetics)
• Nuclear Proteins (genetics)
• Orexins
• Peptides (genetics, metabolism)
• Promoter Regions, Genetic (genetics)
• Rats
• Rats, Sprague-Dawley
• Repressor Proteins (genetics)
• Sleep, REM (genetics)
• Up-Regulation (genetics)
• Wakefulness (genetics)