Decreased Neuronal Excitability in an ApoC2-Deficient Hamster Hypertriglyceridemia Model with Acute Seizure

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The aim of this study is to use genetically modified hamsters with hypertriglyceridemia (HTG) to investigate the effects of high triglycerides on neuronal excitability and to characterize the mechanisms of these effects. Then, to identify novel therapeutic targets for the treatment of neonatal seizures. Acute seizure model was generated by intraperitoneal injection of pentylenetetrazol (PTZ) in homozygous ApoC2 knockout hamsters (ApoC2 −/− ). The number of tonic-clonic seizures was observed. Excitatory postsynaptic potentials (EPSPs) and action potentials (APs) of pyramidal neurons in the frontal cortex were recorded in wild-type and ApoC2 −/− hamsters. HE staining and Nissl staining were performed to observe neuronal morphology of the frontal cortex. Fatty acid metabolomic analysis was applied to microdialysate from the frontal cortex after seizures, and mRNA changes were investigated as well. The frequency of grade IV/V seizures was higher in wild-type hamsters than in ApoC2 −/− hamsters. Additionally, frequencies of EPSPs and APs were significantly lower in ApoC2 −/− hamsters than in wild-type hamsters. Free palmitic acid in the frontal cortex dialysate showed a significant decrease in ApoC2 −/− hamsters compared to wild-type hamsters after PTZ injection. Palmitoyl acyltransferase (PAT) ZDHHC14 expression in the frontal cortex was higher in ApoC2 −/− hamsters than in wild-type hamsters. In ApoC2 −/− model, the frequency of PTZ-induced seizures reduced, and the excitability of neurons decreased; we also found a significant decrease in free palmitic acid levels and observed an upregulation of ZDHHC14. Overall, our results demonstrated that the physiological environment of high triglycerides regulates neuronal excitability and palmitoylation modification may be involved in this mechanism.

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