Neuronal Degeneration in Canine Narcolepsy

Abstract

Narcolepsy is a lifelong illness characterized by persistent sleepiness, hypnagogic hallucinations, and episodes of motor paralysis called cataplexy. We have tested the hypothesis that a transient neurodegenerative process is linked to symptom onset. Using the amino-cupric silver stain on brain sections from canine narcoleptics, we found elevated levels of axonal degeneration in the amygdala, basal forebrain (including the nucleus of the diagonal band, substantia innominata, and preoptic region), entopeduncular nucleus, and medial septal region. Reactive neuronal somata, an indicator of neuronal pathology, were found in the ventral amygdala. Axonal degeneration was maximal at 2-4 months of age. The number of reactive cells was maximal at 1 month of age. These degenerative changes precede or coincide with symptom onset. The forebrain degeneration that we have observed can explain the major symptoms of narcolepsy.Key words: narcolepsy; REM sleep; amygdala; basal forebrain; canine; amino-cupric silver; degeneration; cataplexy Narcolepsy, which occurs at a rate of 0.2-1.6 per thousand (Aldrich, 1990;Hublin et al., 1994), was first recognized 118 years ago by Gélineau (Passouant, 1976). Its symptoms include excessive daytime sleepiness, hypnagogic hallucinations (dream-like mentation in waking), REM sleep at sleep onset, cataplexy (a loss of muscle tone in waking, usually triggered by sudden, strong emotions), and sleep paralysis (an inability to move at sleep onset or awakening) . Narcolepsy has been reported in horses, cattle, and dogs (Mitler et al., 1976; Strain et al., 1984). C anine narcoleptics have been intensively studied. Like human narcoleptics, they are excessively sleepy and have cataplexy. Symptoms in canine and human narcoleptics display a similar response to pharmacological agents Nishino and Mignot, 1997). The cause of narcolepsy is unknown.Narcolepsy is not a progressive disease, in that once symptoms have become f ully established, in both human and canine narcoleptics, they do not become worse (or markedly better) with age. This suggests that narcolepsy may be caused by a transient degenerative process. E xaminations of postmortem tissue in human narcoleptics have not produced consistent evidence for degenerative changes. However, symptom onset is typically 50 or more years before autopsy, a sufficient interval for the removal of any debris resulting from degeneration at the time of disease onset. The age of onset of canine narcolepsy is between 1 and 4 months. In the current study, we have used the amino-cupric stain (de Olmos et al., 1994), an extremely sensitive indicator of degenerating neurons and axons (Switzer, 1991;Fix et al., 1996), to test the hypothesis that narcolepsy onset is linked to neuronal degeneration. MATERIALS AND METHODSEighteen Doberman pinscher dogs, nine narcoleptic and nine age-and breed-matched controls (four male narcoleptics and seven male controls), from six narcoleptic and five normal litters ranging from 1 to 8 months of age were used (Table 1). Control and narcole...

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