Transcriptomic and Proteomic Changes in the Brain Along with Increasing Phenotypic Severity in a Rat Model of Neonatal Hyperbilirubinemia
Abstract
1. Introduction
2. Results
2.1. Evident Severe Motor Deficits in Severe-Phenotype (SP) Gunn Rats
2.1.1. Beam-Walking Test
2.1.2. Cerebellar Hypoplasia
2.1.3. Parietal Motor Cortex Damage at the Microscopic Level
2.2. Genes Associated with Synaptic Plasticity, Cell Proliferation and Differentiation, and Neuronal Development Are Significantly Modulated in SP Animals and Are Correlated with Motor Performance
2.2.1. Genes Significantly Modulated in SP vs. LP
2.2.2. Genes Expressed in SP with Statistical Difference vs. NJ Only and Genes Expressed with Consistent Trends Along the Worsening Phenotypes
2.2.3. Other Genes
2.2.4. Gene Correlations with Motor Performance
2.2.5. Gene Clustering Analysis
2.2.6. Gene Network Analysis
2.3. Proteomic Analysis Confirms Significant Modulations in the Synaptic Plasticity, Cell Proliferation and Differentiation, and Neuronal Development of SP Animals
2.4. Total Serum Bilirubin (TSB) Concentration and Brain Bilirubin (BrB) Content Do Not Fully Explain the Severe Motor Dysfunction
2.4.1. TSB and BrB in Adult Animals
2.4.2. TSB and BrB from the Early Postnatal Age to Adult Life
3. Discussion
4. Materials and Methods
4.1. Animals
4.2. Behavioral Tests
4.3. Cerebellar Weight
4.4. Histology
4.5. Immunofluorescence Microscopy
4.6. Gene Expression Analysis
4.7. Western Blot
4.8. ZIP12 (SLC39A12) ELISA Detection
4.9. Bilirubin Quantification
Total Serum Bilirubin
4.10. Brain Bilirubin Measurement
4.11. Statistical Analyses
4.12. Correlation Analyses
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
ABE | Acute Bilirubin Encephalopathy |
AKT | Protein kinase B |
AMPA | α-Ammino-3-idrossi-5-Metil-4-isossazol-Propionic Acid |
AMPK | Adenosine Monophosphate-activated protein Kinase |
Arhgap4 | Rho GTPase-activating protein 4 |
BG | Bergmann glia |
Bmp5 | Bone morphogenetic protein 5 |
BrB | Brain bilirubin |
Cacna2d4 | Calcium voltage-dependent calcium channel complex alpha-2/delta subunit family |
Camlg | Calcium modulating ligand |
Casp6 | Caspase 6 |
Cll | Cerebellum |
CNS | Central Nervous System |
Col4a3 | Collagenase 4a3 |
CYP | Cytochrome P450 |
Cyp1a1 | Cytochrome P450 1a1 |
Cyp1a2 | Cytochrome P450 1a2 |
Cyp2a3 | Cytochrome P450 2a3 |
CP | Cerebral palsy |
DAG | Diacylglycerol |
ECM | Extracellular matrix |
ERK | Extracellular signal-Regulated Kinase |
fCtx | Frontal cortex |
FoxO | Forkhead box O |
GABA | Gamma-AminoButyric Acid |
GFAP | Glial Fibrillary Acid Protein |
GL | Granular Layer |
Grm1 | Glutamatergic metabotropic receptor 1 |
hCtx | Parietal cortex |
Hyal4 | Hyaluronic acid 4 |
IP3 | Inositol-1,4,5-triphosphate |
ISTD | Internal standard |
jj | Hyperbilirubinemic |
KSD | Kernicterus Spectrum Disorder |
LDH | Lactate dehydrogenase |
LTD | Long-Term Depression |
LTP | Long-Term Potentiation |
LP | Low Phenotype |
MBR | Mesobilirubin |
ML | Molecular Layer |
MRI | Magnetic Resonance Imaging |
Ndufb8 | NADH-ubiquinone oxidoreductase complex 1 subunit 8 |
Ndufs7 | NADH-ubiquinone oxidoreductase complex 1 subunit 7 |
NeuN | Neuronal Nuclear Antigen and Neuron Differentiation Marker |
NF-κB | Nuclear factor kappa B |
NJ | Normobilirubinemic |
NMDA | N-methyl-D-aspartic acid |
Ntsr1 | Neurotensin receptor 1 |
PCs | Purkinje cells |
Pfkfb1 | 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 1 |
PI3K | Phosphatidylinositol 3-kinase |
PKA | Protein Kinase A |
PKC | Protein Kinase C |
Ptn | Pleiotrophin |
P2 | Postnatal day 2 |
P17 | Postnatal day 17 |
ROS | Reactive Oxygen Species |
Slc39a12 | Solute carrier family 39 member 12 |
Slit3 | Slit guidance ligand 3 |
SPF | Specific-Pathogen-Free |
SP | Severe Phenotype |
Thbs2 | Thrombospondin 2 |
Tnr | Tenascin r |
TRPCs | Transient Receptor Potential Canonical proteins |
TSB | Total Serum Bilirubin |
UCB | Unconjugated bilirubin |
UDPGT | UDP glucuronyltransferase |
UGT1A1 | Uridine diphosphate-glucuronosyltransferase 1A1 |
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Biological Process | Gene | Short Description | References |
---|---|---|---|
Migration, Differentiation, Morphogenesis | Slit3 | Acts as chemo-repellents in axonal guidance | [25] |
Tnr | Neuron and neurite growth, synapse maintenance, oligodendrocyte differentiation, regulates astrocyte glutamate uptake in adult brain | [25,26,27,28] | |
Casp6 | Apoptosis, important for achieving the final architecture of the mature, functional central nervous system (CNS). | [19,24,29,30,31,32] | |
Thbs2 | Presynaptic formation during development, cell–cell and cell–matrix interactions; compartmentalization of the extracellular matrix | [25,33,34,35] | |
Arhgap4 | Neurogenesis, synaptogenesis, development, inhibition of cell motility and axon outgrowth and repair during brain development and synaptic plasticity by inhibiting cell and axon motility and regulation of actin. | [24,36,37,38,39,40,41,42,43] | |
Extracellular Matrix (ECM) | Col4a3 | Neuronal development and overall structure of the brain | [25,44,45] |
Hyal4 | Extracellular matrix component, limits lateral diffusion of AMPA receptors; promotes activity of L-type Ca2+ channels | [25,46,47] | |
Synaptogenesis, Synaptic activity, Neuronal circuits establishment | Thbs2 | Presynaptic formation during development, cell–cell and cell–matrix interactions; compartmentalization of the extracellular matrix | [25,33,34,35] |
Cacna2d4 | Voltage-gated calcium channel, with the α2δ subunits as important regulators of synapse formation | [27,48] | |
Bmp5 | Extension and survival of dendrites | [46,47,49] | |
Grm1 | Glutamate neurotoxicity, intracellular signals via interactions with G proteins, and synaptic activity. Glutamate is one of the major neurotransmitters in the brain and is relevant to brain development, with glutamate neurotoxicity considered one of the principal mechanisms of bilirubin neurotoxicity; it has been involved in autism, schizophrenia, and bipolar disorders. | [19,27,48,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65] | |
Ntsr1 | G-protein-coupled receptors relevant to synaptogenesis, plasticity, and neuronal circuity. Neurotensin that acts on its receptor is involved in increased synaptic excitability in different mesencephalic and dopamine cortical neurons via glutamate outflow enhancement and glutamate receptor activation, which subsequently amplifies glutamate-induced neurotoxicity | [27,50,55,58,59,61,65,66,67,68,69,70,71,72,73,74,75] | |
Camlg | Membrane trafficking of postsynaptic GABAA receptors | [48,60] | |
Slit3 | Acts as chemo-repellent in axonal guidance | [25] | |
Arhgap4 | Neurogenesis, synaptogenesis, development, inhibition of cell motility and axon outgrowth and repair during brain development and synaptic plasticity by inhibiting cell and axon motility and regulation of actin. | [24,36,37,38,39,40,41,42,43] | |
Repair Plasticity | Bmp5 | Extension and survival of dendrites | [46,47,49] |
Ntsr1 | G-protein-coupled receptors relevant to synaptogenesis, plasticity, and neuronal circuity. Neurotensin that acts on its receptor is involved in increased synaptic excitability in different mesencephalic and dopamine cortical neurons via glutamate outflow enhancement and glutamate receptor activation, which subsequently amplifies glutamate-induced neurotoxicity | [27,50,55,58,59,61,65,66,67,68,69,70,71,72,73,74,75] | |
Ptn | Repair and plasticity | [76,77,78,79] | |
Energy | Ndufs7/8 | Important subunit of mitochondrial respiratory chain crucial for atp production | [27,80,81,82] |
Pfkfb1 | Catalyzes both the synthesis (glycolysis) and degradation (gluconeogenesis) of fructose-2,6-biphosphate. | [83,84] | |
Behavior | Camlg | Membrane trafficking of postsynaptic GABAA receptors | [48,60] |
Grm1 | Glutamate neurotoxicity, intracellular signals via interactions with G proteins, and synaptic activity. Glutamate is one of the major neurotransmitters in the brain and is relevant to brain development, with glutamate neurotoxicity considered one of the principal mechanisms of bilirubin neurotoxicity; it has been involved in autism, schizophrenia, and bipolar disorders. | [19,27,48,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65] | |
Slc39a12 | Zn transporter involved in control of gene transcription, growth, development, and differentiation, postsynaptic and neuronal circuit functions. Increased ZIP12 would increase cytoplasmic Zn2+ in the extracellular space and intracellular compartments and induce zinc neurotoxicity. It has been involved in schizophrenia. | [85,86,87] | |
Cacna2d4 | Voltage-gated calcium channel, with the α2δ subunits as important regulators of synapse formation | [27,48] | |
Tnr | Neuron and neurite growth, synapse maintenance, oligodendrocyte differentiation, regulates astrocyte glutamate uptake in adult brain | [25,26,27,28] | |
Bilirubin oxidation | Cyp1a1, 1a2, 2a3 | Bilirubin oxidation | [20,88] |
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Llido, J.P.; Valerio, G.; Křepelka, D.; Dvořák, A.; Bottin, C.; Zanconati, F.; Regalado, J.T.; Franceschi Biagioni, A.; Qaisiya, M.; Vítek, L.; et al. Transcriptomic and Proteomic Changes in the Brain Along with Increasing Phenotypic Severity in a Rat Model of Neonatal Hyperbilirubinemia. Int. J. Mol. Sci. 2025, 26, 6262. https://doi.org/10.3390/ijms26136262
Llido JP, Valerio G, Křepelka D, Dvořák A, Bottin C, Zanconati F, Regalado JT, Franceschi Biagioni A, Qaisiya M, Vítek L, et al. Transcriptomic and Proteomic Changes in the Brain Along with Increasing Phenotypic Severity in a Rat Model of Neonatal Hyperbilirubinemia. International Journal of Molecular Sciences. 2025; 26(13):6262. https://doi.org/10.3390/ijms26136262
Chicago/Turabian StyleLlido, John Paul, Giorgia Valerio, David Křepelka, Aleš Dvořák, Cristina Bottin, Fabrizio Zanconati, Julia Theresa Regalado, Audrey Franceschi Biagioni, Mohammed Qaisiya, Libor Vítek, and et al. 2025. "Transcriptomic and Proteomic Changes in the Brain Along with Increasing Phenotypic Severity in a Rat Model of Neonatal Hyperbilirubinemia" International Journal of Molecular Sciences 26, no. 13: 6262. https://doi.org/10.3390/ijms26136262
APA StyleLlido, J. P., Valerio, G., Křepelka, D., Dvořák, A., Bottin, C., Zanconati, F., Regalado, J. T., Franceschi Biagioni, A., Qaisiya, M., Vítek, L., Tiribelli, C., & Gazzin, S. (2025). Transcriptomic and Proteomic Changes in the Brain Along with Increasing Phenotypic Severity in a Rat Model of Neonatal Hyperbilirubinemia. International Journal of Molecular Sciences, 26(13), 6262. https://doi.org/10.3390/ijms26136262