Effect Of BMP4 And Noggin On Neurogenesis Of Hippocampus And Epileptogenesis In KA Rat Models Of Epilepsy

Epilepsy is a common disease of nervous system characterized by functional imbalance of brain caused by repeated abnormal electric-release from neural cells in brain. According to many large amount investigations, the cumulative incidence rate is about 5‰. With the development of anti-epileptic drugs in recent years, most epileptic patients can be well controlled with regular treatment, while about 20%~30% patients develop to intractable epilepsy. 70% of them are temporal lobe epilepsy. The extended frequent and severe epileptic seizures bring about great pain to the patients and their families. But up to now, the pathogenesis of epilepsy is still not clear.There are many theories about epilepsy today, trying to explain epileptic pathogenesis. Since Scharfman first brought forward that the neurogenesis mechanism was concerned with the epileptic pathogenesis, many researches in the neurogenesis of epilepsy were carried out throughout the world.Previous studies showed that granule cell neurogenesis occurs in the dentate gyrus of the adult rodent. Neurons are born in the underlying subgranular layer and move into the granule cell layer (GCL) to become mature granule neurons. Evidences have demonstrated that adult hippocampus neurogenesis was increased dramatically after seizures. Recent results supported the hypothesis that newly-born granule cells might not necessarily act to ameliorate seizure, and might even contribute to seizures.It has been reported that KA animal models of epilepsy stimulated DG cell neurogenesis, while the molecular mechanism underlying has not been made clear.Additionally, several studies suggest that multiple growth factors and hormones, including basic fibroblast growth factor (bFGF), epidermal growth factor, adrenal steroids, and estrogen, may influence neuronal production in developing and young adult rodents. Precise control of bone morphogenetic protein-4 (BMP4) signaling in the extracellular space appears to play a critical role in multiple events during development, including neural induction,tissue patterning,epithelial-mesenchymal interactions underlying organogenesis, lineage selection and in the creation of stem cell "niches" in developing and adult organs. It has been demonstrated that both BMPs and their receptors were expressed in adult hippocampus. A moderate increase in BMPRII mRNA expression was observed in granule cells of the DG after both mild head trauma and cerebral ischemia, which suggested that BMPs might modulate hippocampal plasticity. Noggin belongs to a class of polypeptides that bind to bone morphogenetic proteins (BMPs) and consequently prevent their activation of BMP receptors (BMPRs). It has been demonstrated that noggin antagonizes bone morphogenetic protein-4 (BMP4) to create a niche for subventricular zone neurogenesis. FAN have demonstrated that noggin and BMP4 were found in the proliferative subgranular layer of the dentate gyrus in postnatal rats. Previous study showed that noggin ASODN treatment decreases the rate of cell proliferation in the dentate gyrus significantly.This indicated that endogenous noggin activity is important for neurogenesis in the dentate gyrus in adult rat. But we do not know if noggin play the same role in neurogenesis in the dentate gyrus after KA-induced seizures.The kainic acid animal models of epilepsy are one of the most common experimental tools in epilepsy research . In adult rats, i.c.v. administration of kainic acid, an agonist of the kainic acid subtype of glutamate receptor, leads to status epilepticus, which lasts for several hours. Several days to weeks after status, spontaneous limbic seizures often occur and continue intermittently thereafter.Granule cell progenitors in the dentate gyrus of the hippocampal formation have the unusual capacity to be able to divide in the brains of adult rats and primates. Previous study have demonstrated that Kainic acid can increases the proliferation of granule cell progenitors in the dentate gyrus of the adult rat. The mechanisms by which seizure activity may induce increased granule cell neurogenesis and neural plasticity remain unknown.We hypothesised that BMP4 and noggin might affect dentate granule cell neurogenesis and neural plasticity after kainic acid -induced seizures. To test this hypothesis , the present study was designed to investigate the time-dependent alternation in expression level of BMP4 and noggin and explore its correlation with neural proliferation and neural plasticity using BrdU labeled technique. Then we have used i.c.v. injection of ASODN to BMP4 and noggin to study the relationship between the expression of BMP4 and noggin and the neuronal proliferation and neural plasticity in the dentate gyrus of adult rats after a unilateral i.c.v. injection of kainic acid. Third,in the in vitro study,the effect of BMP4 and noggin on the neurogenesis and differentiation of hippocampal NSCs was explored.The main results are as followed.1. BMP4 and noggin are expressed in hippocampus in normal adult rats.2. The neurogenesis,mossy fiber sprouting(MFS),Hilar ectopic granule cells (HEGCs) , gliosis in hippocampus are significantly increased after i.c.v. administration of KA, 2 months later the SRS appears gradually.The kainic acid-induced model is an ideal animal model simulating human temporal lobe epilepsy in pathology and ethology.3. The expression of BMP4 and noggin in dentate gyrus are significantly increased after i.c.v. administration of KA. The expression of BMP4 reaches the top level 1 day after injection of KA,the expression of noggin reaches the top level 3 day after injection of KA, then declined to base level 2 months later.4. BMP4 can inhibit the neurogenesis,MFS,HEGCs in hippocampus,and decrease the SRS during temporal lobe epileptogenesis.Noggin can promote the neurogenesis, MFS,HEGCs in hippocampus,and increase the SRS during temporal lobe epileptogenesis by antagonizing the effect of BMP4.5. In vitro study demonstrates that BMP4 can inhibit the cell proliferation of hippocampal NSCs, and promote the differentiation of neuron, noggin can promote the cell proliferation of hippocampal NSCs, and promote the differentiation of neuron by antagonizing the effect of BMP4.In conclusion,we have studied the expression of BMP4/noggin in the hippocampus during temporal lobe epileptogenesis,and the effect of BMP4/noggin on neurogenesis , MFS, HEGCs and SRS.In vitro,we have studied the effect of BMP4/noggin on the proliferation and differentiation of hippocampal NSCs. It is demonstrated that the expression of BMP4/noggin are increased after i.c.v. injection of KA,the interaction and concentration gradient of BMP4 /noggin promote the neurogenesis,MFS,HEGCs in hippocampus,and increase the SRS during temporal lobe epileptogenesis.