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Excitotoxic stimulation activates distinct pathogenic and protective expression signatures in the hippocampus |
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| Authors: | Ebru Caba Marcus D. Sherman Karen L. G. Farizatto Britney Alcira Hsin-wei Wang Charles Giardina Dong-Guk Shin Conner I. Sandefur Ben A. Bahr |
| Affiliation: | 1. Vertex Pharmaceuticals, Cambridge, MA, USA Department of Pharmaceutical Sciences and the Neurosciences Program, University of Connecticut, Storrs, CT, USA Contribution: Conceptualization (equal), Data curation (equal), Formal analysis (supporting), Investigation (equal), Methodology (equal), Writing - original draft (equal);2. Biotechnology Research and Training Center, University of North Carolina-Pembroke, Pembroke, NC, USA Department of Biology, University of North Carolina-Pembroke, Pembroke, NC, USA Contribution: Data curation (equal), Formal analysis (equal), Methodology (equal);3. Biotechnology Research and Training Center, University of North Carolina-Pembroke, Pembroke, NC, USA Department of Biology, University of North Carolina-Pembroke, Pembroke, NC, USA Contribution: Data curation (supporting), Investigation (supporting);4. Bioinformatics and Biocomputing Institute, University of Connecticut, Storrs, CT, USA Department of Computer Science and Engineering, University of Connecticut, Storrs, CT, USA Contribution: Data curation (equal), Formal analysis (equal);5. Department of Molecular and Cell Biology, University of Connecticut, Storrs, CT, USA Contribution: Methodology (equal), Supervision (equal);6. Bioinformatics and Biocomputing Institute, University of Connecticut, Storrs, CT, USA Department of Computer Science and Engineering, University of Connecticut, Storrs, CT, USA Contribution: Conceptualization (equal), Investigation (equal), Methodology (equal), Supervision (equal);7. Department of Biology, University of North Carolina-Pembroke, Pembroke, NC, USA Department of Pharmacology and the Cystic Fibrosis and Pulmonary Diseases Research and Treatment Center, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA Sandefur Modeling, Pittsboro, NC, USA Contribution: Data curation (equal), Formal analysis (equal), Methodology (equal), Supervision (equal);8. Department of Pharmaceutical Sciences and the Neurosciences Program, University of Connecticut, Storrs, CT, USA |
| Abstract: | Excitotoxic events underlying ischaemic and traumatic brain injuries activate degenerative and protective pathways, particularly in the hippocampus. To understand opposing pathways that determine the brain's response to excitotoxicity, we used hippocampal explants, thereby eliminating systemic variables during a precise protocol of excitatory stimulation. N-methyl-d -aspartate (NMDA) was applied for 20 min and total RNA isolated one and 24 h later for neurobiology-specific microarrays. Distinct groups of genes exhibited early vs. delayed induction, with 63 genes exclusively reduced 24-h post-insult. Egr-1 and NOR-1 displayed biphasic transcriptional modulation: early induction followed by delayed suppression. Opposing events of NMDA-induced genes linked to pathogenesis and cell survival constituted the early expression signature. Delayed degenerative indicators (up-regulated pathogenic genes, down-regulated pro-survival genes) and opposing compensatory responses (down-regulated pathogenic genes, up-regulated pro-survival genes) generated networks with temporal gene profiles mirroring coexpression network clustering. We then used the expression profiles to test whether NF-κB, a potent transcription factor implicated in both degenerative and protective pathways, is involved in the opposing responses. The NF-κB inhibitor MG-132 indeed altered NMDA-mediated transcriptional changes, revealing components of opposing expression signatures that converge on the single response element. Overall, this study identified counteracting avenues among the distinct responses to excitotoxicity, thereby suggesting multi-target treatment strategies and implications for predictive medicine. |
| Keywords: | compensatory signalling excitotoxic response gene array neuroprotection repair pathway transcription factor |