The development of hypocretin (orexin) deficiency in hypocretin/ataxin-3 transgenic rats.
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.
Zhang
S
S
Stanford University, 701 Welch Road, Room 145, Palo Alto, CA 94304-5742, USA.
Lin
L
L
Kaur
S
S
Thankachan
S
S
Blanco-Centurion
C
C
Yanagisawa
M
M
Mignot
E
E
Shiromani
P J
PJ
D000375:Aging / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D000067699:Ataxin-3; D004195:Disease Models, Animal; D005260:Female; D007031:Hypothalamus / Q000378:metabolism / Q000503:physiopathology*; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000134:cerebrospinal fluid / Q000235:genetics*; D008297:Male; D009290:Narcolepsy / Q000134:cerebrospinal fluid / Q000235:genetics / Q000503:physiopathology*; D009410:Nerve Degeneration / Q000134:cerebrospinal fluid / Q000235:genetics / Q000503:physiopathology*; D009419:Nerve Tissue Proteins / Q000235:genetics; D009474:Neurons / Q000378:metabolism*; D009479:Neuropeptides / Q000134:cerebrospinal fluid / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D000068797:Orexins; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012097:Repressor Proteins / Q000235:genetics; D012895:Sleep, REM / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics; D014851:Wakefulness / Q000235:genetics
D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D009687:Nuclear Proteins; D000068797:Orexins; D010455:Peptides; D012097:Repressor Proteins; C097188:polyglutamine; C092341:ATXN3 protein, human; D000067699:Ataxin-3