Changes in lipid profiles of epileptic mouse model

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.

Keywords: Drug resistant epilepsy; Lipids; Metabolic profiling; Metabolomics; Seizure.

Fig. 1

a Venn Diagram showing the uniqueness and overlap of all features. b Hierarchical clustering based on all features from each tissue. c PLS-DA score plots comparing the lipidomic profiles between hippocampal and cortical tissue in addition to wild-type vs. KV1.1−/−

Fig. 2

a Volcano plot of all features in the hippocampus. Compounds with a log2 fold change of > 2 (KO/WT) and a p value < 0.05 have been highlighted in pink. b PLS-DA scores plots comparing lipidomic profiles between Kv1.1−/− and WT mice in the hippocampus. c Heatmap detailing significant features in the hippocampus and the overall trend of upregulation in response to Kv1.1 knockout. Correlation of these features can also be seen by hierarchical clustering

Fig. 3

a Volcano plot of all features in the cortex. Compounds with a log2 fold change (KO/WT) of > 2 and a p value < 0.05 have been highlighted in pink. b PLS-DA scores plot comparing lipid changes in Kv1.1−/− and WT cortex tissue in mice. c Heatmap detailing significant features found in the cortex and overall trend of downregulation in response to Kv1.1 knockout. Correlation of these features are also shown by hierarchical clustering

Fig. 4

a Affected pathways generated from KEGG ID input show that overall metabolism of lipids is impacted. b Phospholipid metabolic pathways comprise a majority of lipid metabolism pathways affected, namely synthesis and remodeling pathways. All pathways highlighted are significant (adjusted p < 0.05)

Fig. 5

Comprehensive look of all tentatively identified significant lipid species found in each analysis described in this study and their respective fold changes (i.e. cortex, tissue, and partition ratio). “*” indicates that the species in question was significantly (p < 0.05) changed within the specified group only. All Fold Changes expressed as Log2 fold change