Kernicterus spectrum disorder is the permanent and highly disabling neurologic sequel of neonatal exposure to hyperbilirubinemia, presenting, among other symptoms, variable and untreatable motor disabilities. To search for potential biomolecular explanations, we used a Gunn rat colony exhibiting spontaneous hyperbilirubinemia and a large variability of motor deficits on a beam-walking test. Histological and microscopic analyses confirmed worsening damage in the cerebellum (Cll; hypoplasia, increased death of neurons, and disrupted astroglial structures) and parietal motor cortex (hCtx; increased cell sufferance and astrogliosis). Clustering and network analyses of transcriptomic data reveal rearrangement of the physiological expression patterns and signaling pathways associated with bilirubin neurotoxicity. Bilirubin content among hyperbilirubinemic (jj) animals is overlapped, which suggests that the amount of bilirubin challenge does not fully explain the tissue, transcriptomic, proteomic, and neurobehavioral alterations. The expression of nine genes involved in key postnatal brain development processes is permanently altered in a phenotype-dependent manner. Among them, Grm1, a metabotropic glutamatergic receptor involved in glutamate neurotoxicity, is consistently downregulated in both brain regions both at the transcriptomic and proteomic levels. Our results support the role of Grm1 and glutamate as biomolecular markers of ongoing bilirubin neurotoxicity, suggesting the possibility to improve diagnosis by 1H-MR spectroscopy.

4th Department of Internal Medicine General University Hospital Prague 1st Faculty of Medicine Charles University 12108 Prague Czech Republic

Cognitive Neuroscience Department International School for Advanced Studies Via Bonomea 265 34136 Trieste Italy

Department of Life Sciences University of Trieste 34139 Trieste Italy

Department of Medical Laboratory Science Hebron University Hebron P785 Palestine

Department of Medical Surgical and Health Sciences University of Trieste 34127 Trieste Italy

Department of Science and Technology Philippine Council for Health Research and Development Bicutan Taguig City 1631 Philippines

Institute of Medical Biochemistry and Laboratory Diagnostics General University Hospital Prague 1st Faculty of Medicine Charles University 12108 Prague Czech Republic

The Liver Brain Unit Rita Moretti Fondazione Italiana Fegato Onlus Bldg Q AREA Science Park 34149 Basovizza Italy

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