Abstract
Introduction
Approximately 1% of the world’s population is impacted by epilepsy, a chronic neurological disorder characterized by seizures. One-third of epileptic patients are resistant to AEDs, or have medically refractory epilepsy (MRE). One non-invasive treatment that exists for MRE includes the ketogenic diet, a high-fat, low-carbohydrate diet. Despite the KD’s success in seizure attenuation, it has a few risks and its mechanisms remain poorly understood. The KD has been shown to improve metabolism and mitochondrial function in epileptic phenotypes. Potassium channels have implications in epileptic conditions as they have dual roles as metabolic sensors and control neuronal excitation.
Objectives
The goal of this study was to explore changes in the lipidome in hippocampal and cortical tissue from Kv1.1-KO model of epilepsy.
Methods
FT-ICR/MS analysis was utilized to examine nonpolar metabolome of cortical and hippocampal tissue isolated from a Kv1.1 channel knockout mouse model of epilepsy (n = 5) and wild-type mice (n = 5).
Results
Distinct metabolic profiles were observed, significant (p < 0.05) features in hippocampus often being upregulated (FC ≥ 2) and the cortex being downregulated (FC ≤ 0.5). Pathway enrichment analysis shows lipid biosynthesis was affected. Partition ratio analysis revealed that the ratio of most metabolites tended to be increased in Kv1.1−/−. Metabolites in hippocampal tissue were commonly upregulated, suggesting seizure initiation in the hippocampus. Aberrant mitochondrial function is implicated by the upregulation of cardiolipin, a common component in the mitochondrial membrane.
Conclusion
Generally, our study finds that the lipidome is changed in the hippocampus and cortex in response to Kv1.1-KO indicating changes in membrane structural integrity and synaptic transmission.
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Acknowledgements
This work was supported by grants from the National Institute of Health (P20 RR017675, P20 GM104320, NS085389, NS072179 and NS111389) and from Citizens United for Research in Epilepsy Foundation.
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A.J., R.A.G., D.M., C.H.T.B., H.K. and K.Sa. carried out experiments; A.J., R.A.G., D.M., C.H.T.B., C.B., K.Si., T.S., T.H., C.K.H. and J.A. performed data analysis and interpretation; A.J. and J.A. wrote paper with input from all the authors.
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11306_2020_1729_MOESM2_ESM.docx
Supplementary material 2 (DOCX 24 kb) Supplementary Table 1. The 66 significant (p<0.05) features identified in the hippocampus. A majority were found to be elevated in Kv1.1-/- mice compared to WT mice. *Provided annotation represent simple m/z based fit and can be affected by in source fragmentation. Therefore, it is important to note that all identifications are tentative, and their validation would require additional characterization involving purified standards and extensive MSn analysis
11306_2020_1729_MOESM3_ESM.docx
Supplementary material 3 (DOCX 24 kb) Supplementary Table 2. 72 significant (p<0.05) features identified in the cortex with almost all compounds being downregulated in the Kv1.1 -/- compared to the WT. Retention times and m/z have been included
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Supplementary material 4 (DOCX 12 kb) Supplementary Table 3. Pathways that were significantly (adj. p<0.05) affected via Reactome pathway database search
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Supplementary material 5 (XLSX 11 kb) Supplementary Table 4. Statistical Data from multivariate analysis performed using one-way ANOVA analysis.
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Johnson, A., Grove, R.A., Madhavan, D. et al. Changes in lipid profiles of epileptic mouse model. Metabolomics 16, 106 (2020). https://doi.org/10.1007/s11306-020-01729-4
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DOI: https://doi.org/10.1007/s11306-020-01729-4