Hypocretin levels in sporadic and familial cases of canine narcolepsy

Familial and sporadic forms of narcolepsy exist in both humans and canines. Mutations in the hypocretin receptor 2 gene (Hcrtr 2) cause canine familia l narcolepsy. In humans, mutations in hypocretin-related genes are rare, bu t cerebrospinal fluid (CSF) hypocretin-1 is undetectable in most sporadic c ases. Using the canine model, we investigated (1) whether hypocretin defici ency is involved in sporadic cases and (2) whether alterations in hypocreti n neurons or ligand levels also contribute to the phenotype in Hcrtr 2 muta nts. We found that hypocretins were undetectable in the brains of three of three and the CSF of two of two sporadic narcoleptic dogs tested. In contra st, hypocretin levels were not altered in brains and CSF of genetically nar coleptic Dobermans, and hypocretin-containing neurons were of normal appear ance. Therefore, multiple hypocretin-related etiologies are likely to be in volved in canine narcolepsy. The presence of hypocretin peptides in Hcrtr P -mutated animals suggests that neurotransmission through Hcrtr 1 may be int act, arguing for a preferential importance of Hcrtr 2-mediated function in narcolepsy. (C) 2001 Academic Press.