Abstract
Cyclothiazide (CTZ) has been reported to simultaneously enhance glutamate receptor excitation and inhibit GABAA receptor inhibition, and in turn it evokes epileptiform activities in hippocampal neurons. It has also been shown to acutely induce epileptic seizure behavior in freely moving rats. However, whether CTZ induced seizure rats could develop to have recurrent seizure still remains unknown. In the current study, we demonstrated that 46% of the CTZ induced seizure rats developed to have recurrent seizure behavior as well as epileptic EEG with a starting latency between 2 weeks and several months. In those chronic seizure rats 6 months after the seizure induction by the CTZ, our immunohistochemistry results showed that both GAD and GAT-1 were significantly decreased across CA1, CA3, and dentate gyrus area of the hippocampus studied. In addition, both BDNF and its receptor TrkB were also decreased in hippocampus of the chronic CTZ seizure rats. Our results indicate that CTZ induced seizure is capable of developing to have recurrent seizure, and the decreased GABA synthesis and transport as well as the impaired BDNF-TrkB signaling pathway may contribute to the development of the recurrent seizure. Thus, CTZ seizure rats may provide a novel animal model for epilepsy study and anticonvulsant drug testing in the future.
Highlights
Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter and exists widely in central nervous system of mammal animals
We investigated whether GABAergic neurons in the hippocampus were affected during epileptogenesis in its chronic phase, by immunostaining of glutamate decarboxylase (GAD), a rate-limiting enzyme in GABA synthesis, and GABA transporters (GAT)-1, a cell membrane localized GABA transporter [18,19,20]
We further investigated whether Brain-derived neurotrophic factor (BDNF)-TrkB signaling pathway was remaining affected in the chronic recurrent phase in CTZ seizure rats
Summary
Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter and exists widely in central nervous system of mammal animals. GABA receptors mediate inhibitory neurotransmission to prevent neurons from being overexcited in adult brain [1]. GABA is synthesized from glutamate by glutamate decarboxylase (GAD), which is a rate-limiting enzyme in GABA synthesis. GABA is released from neurons to synaptic cleft and exerts inhibitory effect. The major cortical GABA transporters (GAT), which uptake the GABA to neurons or glia from synaptic cleft, primarily localized to the presynaptic terminals and to glial processes adjacent to the synaptic cleft. GAT has been reported to participate in GABA releasing to adjust GABA concentration in synaptic cleft [2]
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