ABSTRACT
Kruppel-like factor 4 (Klf4) is a transcription factor that is involved in neuronal regeneration and the development of glutamatergic systems. However, it is unknown whether Klf4 is involved in acute seizure. To investigate the potential role of Klf4 in pentylenetetrazol (PTZ)-induced seizure, western blotting, immunofluorescence, behaviour test and electrophysiology were conducted in this study. We found that Klf4 protein and mRNA expression were increased in both the hippocampus (HP) and prefrontal cortex (PFC) after PTZ-induced seizure in mice. HP-specific knockout (KO) of Klf4 in mice decreased protein expression of Klf4 and the down-stream Klf4 target tumour protein 53 (TP53/P53). These molecular changes are accompanied by increased seizure latency, reduced immobility time in the forced swimming test and tail suspension test. Reduced hippocampal protein levels for synaptic proteins, including glutamate receptor 1 (GRIA1/GLUA1) and postsynaptic density protein 95 (DLG4/PSD95), were also observed after Klf4-KO, while increased mRNA levels of complement proteins were observed for complement component 1q subcomponent A (C1qa), complement component 1q subcomponent B (C1qb), complement component 1q subcomponent C (C1qc), complement component 3 (C3), complement component 4A (C4a) and complement component 4B (C4b). Moreover, c-Fos expression induced by PTZ was reduced by hippocampal conditional KO of Klf4. Electrophysiology showed that PTZ-induced action potential frequency was decreased by overexpression of Klf4. In conclusion, these findings suggest that Klf4 plays an important role in regulating PTZ-induced seizures and therefore constitutes a new molecular target that should be explored for the development of antiepileptic drugs.
Subject(s)
Hippocampus , Kruppel-Like Factor 4 , Kruppel-Like Transcription Factors , Mice, Knockout , Pentylenetetrazole , Seizures , Animals , Kruppel-Like Factor 4/metabolism , Seizures/metabolism , Seizures/chemically induced , Seizures/genetics , Kruppel-Like Transcription Factors/metabolism , Kruppel-Like Transcription Factors/genetics , Mice , Hippocampus/metabolism , Male , Prefrontal Cortex/metabolism , Mice, Inbred C57BL , Disease Models, AnimalABSTRACT
BACKGROUND AND OBJECTIVE: Early afterdepolarizations (EADs) are associated with a variety of arrhythmias and have the property of rate dependence. EADs can occur in Purkinje cells while the effect of rate dependence of EADs in the His-Purkinje system has not been fully investigated. In order to reveal the rate dependence of EADs in the His-Purkinje system and its effect on ventricular electrical activities, the simulation research was carried out in this manuscript. METHODS: This manuscript first studied the relationship between the occurrence of EADs and stimulation cycle length on the DiFranNoble cell model. Then, the relationship between the rate dependence of EADs and the conduction block of the His-Purkinje system at slow heart rates was studied on the rabbit whole ventricular model including the His-Purkinje system, and its mechanism was analyzed from multiple angles. RESULTS: â The rate dependence of EADs is related to the inconsistency of EADs occurrence in the His-Purkinje system. When the stimulation cycle length is long or short enough, EADs either occur or not occur stably in the His-Purkinje system, while in a certain stimulation cycle length window, the chaotic state of EADs will be observed. â¡ The key subcellular factors x-gate is an important mechanism involved to the rate dependence of EADs in the His-Purkinje system. ⢠The discrete distribution of x-gate values and the "source-sink" mechanism lead to the inconsistency of EADs in the His-Purkinje system. The prolonged action potential duration caused by EADs can lead to conduction block at slow heart rates. CONCLUSION: The rate dependence of EADs in Purkinje system can lead to disordered ventricular electrical activity.