Download Loss of orexin/NARP neurons in human narcolepsy

Loss of orexin/NARP neurons in human narcolepsy
R. A. Espana1; A. J. Crocker1; E. Mignot2; J. M. Baraban3; I. M. Reti3; T. E. Scammell1
1
Dept Neurol, Beth Israel Deaconess Med Ctr, Harvard Med Sch, Boston, MA, USA
2
Ctr. For Narcolepsy, Stanford Univ, Palo Alto, CA, USA
3
Dept Psychiat, Johns Hopkins Sch Med, Baltimore, MD, USA
People with narcolepsy have a loss of orexin/hypocretin (ORX) immunoreactivity and
mRNA, and cerebrospinal fluid levels of ORX are often reduced in patients with
cataplexy. Mice and dogs lacking ORX or ORX receptors display narcolepsy-like
symptoms similar to those observed in people. Further, mice and rats with an engineered
loss of ORX neurons have a nearly identical narcolepsy phenotype. Combined, these
observations suggest that ORX is critically involved in narcolepsy and the regulation of
sleep and waking.
Most rat ORX neurons contain neuronal activity-regulated pentraxin (NARP), a secreted
immediate-early gene product important for the recruitment of glutamate receptors. To
examine whether a loss of NARP contributes to human narcolepsy, we examined the
expression of ORX- and NARP-immunoreactivity in the hypothalami of normal humans
and those with narcolepsy. Hypothalami were immunostained using ORX-A and NARP
antisera. Rostrally, ORX- immunoreactive (IR) neurons were observed in the caudal parts
of the paraventricular nucleus and reached a high density in the dorsal hypothalamic area,
dorsomedial nucleus, and perifornical region. Caudally, cells were abundant in the lateral
and posterior hypothalamus. Across the entire ORX field, nearly all ORX-ir neurons
contained NARP-immunoreactivity. In two cases of narcolepsy with cataplexy, the
number of NARP-ir neurons was markedly reduced in this region but not in nearby areas.
Consistent with the previously described focal loss of dynorphin in people with
narcolepsy, these observations further support the hypothesis that narcolepsy is
associated with a loss of the neurons that produce ORX. Additionally, these data suggest
that a loss of NARP may contribute to the symptoms observed in narcolepsy.
Support Contributed By: NIH grants MH62589 and HL02013
Citation: R.A. Espana, A.J. Crocker, E. Mignot, J.M. Baraban, I.M. Reti, T.E. Scammell.
Loss of orexin/NARP neurons in human narcolespy. Program No. 318.2. 2004 Abstract
Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience, 2004. Online.