Abstract 2047 Poster Session II, Sunday, 5/2 (poster 237)

Neonatal hyperbilirubinemia is associated with distinct clinical symptoms, including extrapyramidal motor deficits, gaze deficits, and sensorineural hearing loss. In previous studies, we have demonstrated a substantial reduction in the density of immunoreactive staining for the calcium-binding proteins (CaPBs), calbindin-D28k and parvalbumin, in the jaundiced (jj) Gunn rat at 15-18 days postnatally in the lower brainstem auditory relay nuclei in comparison to non-jaundiced (Nj) littermate control rats. The findings from these studies demonstrated that bilirubin toxicity in the auditory brainstem in the absence of kernicterus lesions produces molecular changes in the expression of CaBPs in the brainstem auditory nuclei that correlate well with electrophysiological deficits in the brainstem auditory evoked responses and the retrochlear sensorineural hearing loss that characterized hyperbilirubinemia.

The present study was undertaken to determine whether other regions of the central nervous system associated with specific neurological deficits similarly are vulnerable to bilirubin toxicity. In Nj Gunn and normal Wistar rats, neurons in the vestibular, oculomotor, and preoculomotor nuclei that discharge at high frequency express parvalbumin, which buffers the influx of calcium accompanying the membrane depolarization that follows the activation of glutamate receptors. In jj Gunn rats, striking decreases in parvalbumin-immunoreactivity are observed in the vestibular complex, the interstitial nucleus of Cajal, and the extraocular motor nuclei. Calbindin-D28k is associated with the inhibitory GABAergic cerebellar Purkinje cell input to neurons in the lateral vestibular nucleus. The expression of both calbindin-D28k and GABA in the lateral vestibular nucleus is reduced substantially in the jaundiced jj rats. These findings are correlated with the motor deficits that are associated with bilirubin toxicity in humans. Collectively, the effects of bilirubin toxicity on the expression of calcium-binding proteins in neurons in brainstem auditory, vestibular, and oculomotor systems are consistent with the demonstration that impaired calcium homeostasis resulting from the loss of calcium-binding proteins is related to cellular and behavioral deficits.

Supported by grants from the American Hearing Research Foundation and the National Institutes of Health (EY02191 and DC00369)