Down-regulated GABA And BDNF-TrkB Pathway And Cofilin Rod Formation In Seizure Model

Epilepsy is one of the most frequent central nervous system (CNS) disorder, with 35/100,000 of morbidity and 0.5% of prevalence rate. There are 30,000,000 epilepsy patients all over the world,25% of which can’t be effectively cured and refered as the refractory epilepsy. The underlied mechanismsis of epileptogenesis are very complex. However, the imbalance between excitation and inhibition in CNS is the basic inductive factor. Ion channel, neurotransmitter or glia may be involved, but the direct epileptogenisis isn’t well known. GABA is main inhibitory neurotransmitter in central nervous system, mediate inihibitory synaptic transmition and prevent overexcitation of neurons. Decreased GABA transmition system induced nerons over excited and epileptogenisis. After epileptogenisis, lots of microglia were activated and proliferated to protect neurons from damage by secreting BDNF. BDNF and its receptor TrkB exert ourstanding positive roles in growth, development and differenciation of neurons. CTZ has long been known as an AMPA receptor desensitization blocker and thus prolongs glutamate excitatory response and increases presynaptic glutamate release to induce epileptiform activity, CTZ has been shown to be a potent convulsant drug. However, whether CTZ can act like pilocarpine or kainic acid to establish a useful behavioral seizure model is still not explored. In this study, we report that microinjection of CTZ into the lateral ventricle induced typical seizure behaviors in freely moving rats. And we continue to study behavior and EEG of CTZ seizure model for 6 months, change of GABA transmition systerm and BDNF-TrkB pathway 6 months after CTZ injection. And to explore activation and proliferation of microglia, apoptosis and cofilin aggregation in brain after KA induced seizure. We found out cofilin rod formation in brain of KA seizure model.In the first part of this thesis, we build a new animal epilepsy model by CTZ injection (i.c.v.). And we also observed seizure behavior and recorded EEG for 6 months after CTZ induced seizure; Changes of GAD, GAT-1,5 subunit of GABAA receptor and BDNF-TrkB pahtway were studied. All results show that microinjection of CTZ into the lateral ventricle induced typical seizure behaviors in freely moving rats; recurrent seizure were observed in 6 months after CTZ injection; function of GABAergic neurons and δ subunit of GABAA receptor decreased, BDNF-TrkB pathway was involved recurrent seizre; and changed RSG in morphology were also found out after seizure.In the second part of this thesis, we studied cofilin expression, activated microglia and proliferation and suiviving of neurons in brain of KA induced seizure model on the 1st,7th,14th and 28th day. Our results suggested that cofilin rod formation on the 7th,14th and 28th day after KA induced seizure. Lots of activated microglia moved to area around cofilin rod. The number of microglia reached peak on the 7th day, and keep high level on the 14th day and the 28th day. Some apoptosis neurons were observed in the brain 24h after KA induced seizure, and more and more neurons exhibited apoptosis until the 28th day. Interestingly, many glias also were observed apoptosis in the 7th day after KA induced seizure.In conclusion, our results demonstrated that microinjection of CTZ into the lateral ventricle induced typical seizure behaviors and recurrent seizure in freely moving rats; GABAergic transmission and BDNF-TrkB expression changed in the chronic stage after CTZ induced seizure. Cofilin rod formation at different stage after seizure; And, lots of activated microglia moved to repair damaged neurons after seizure. GABAergic transmission, BDNF-TrkB pathway, Cofilin aggregation and activated microglia were important for epilepsy development; which may provide a new target and theory for further investigate epilepsy and screening new drugs for treatment.