Synaptic vesicle protein 2A (SV2A) involvement has been reported in the animal models of epilepsy. The aim of this study was to investigate the expression of SV2A in human intractable epilepsy (IE) brain tissue. Using immunohistochemistry, immunofluorescence, and Western blot, we detected SV2A expression in tissue samples from the anterior temporal neocortex of 33 patients who had been surgically treated for IE. We compared these tissues with nine histologically normal anterior temporal lobe samples from controls. SV2A immunoreactive staining was 0.1651+/-0.0564 in patient group and 0.2347+/-0.0187 in the control group (p<0.05) using immunohistochemistry, and this finding was consistently observed with Western blot analysis (0.1727 +/- 0.0471 versus 0.3976+/-0.0983, p<0.05). Immunofluorescence staining showed that SV2A was mainly accumulated in neurons. Our findings demonstrate that down-regulation of SV2A is present in patients with temporal lobe epilepsy.
Approximately 30 % of epilepsy cases are refractory to current pharmacological treatments through unknown mechanisms. Much work has been done on the role of synaptic components in the pathogenesis of epilepsy, but relatively little attention has been given to the potential role of the microtubules. We investigated the level of microtubule dynamic in 30 human epileptic tissues and two different chronic epilepsy rat models. The administration of microtubule-modulating agent attenuated the progression of chronic epilepsy. By contrast, microtubule-depolymerizing agent aggravated the progression of chronic epilepsy. The electrophysiological index by whole-cell clamp was used to investigate the neuronal excitation and inhibitory synaptic transmission in brain slices after administration of microtubule-modulating agent and microtubule-depolymerizing agent. Interestingly, we found that microtubule-modulating agent significantly increased the frequency of action potential firing in interneurons, and significantly promoted the amplitudes and frequencies of miniature inhibitory postsynaptic currents. Microtubule-depolymerizing agent had an opposite effect. These findings suggest that modulating hyperdynamic microtubules may take an anti-epileptic effect via postsynaptic mechanisms in interneurons. It could represent a potential pharmacologic target in epilepsy treatment.
To elucidate the molecular basis of intractable epilepsy (IE), we used a whole-genome transcriptomic approach to identify genes involved in the pathogenesis of this disease. Using a complementary DNAs microarray representing 4096 human genes, we analyzed differential gene expression in the anterior temporal neocortex (ATN) of IE patients relative to control patients who had an operation to relieve head trauma-related intracranial pressure. The results were validated by real-time fluorescence-quantitative polymerase chain reaction (FQ-PCR) and reverse transcription-PCR (RT-PCR). The expression of 143 genes (3.5%) was significantly altered in IE patients. Thirty-seven genes (26%) were reduced relative to controls, and 106 (74%) were elevated (more than twofold change vs. controls), including genes involved in immunity, signal transduction, apoptosis, stress, synaptic plasticity, structural, and cellular reorganization, among other processes. Results for 13 of the 14 differentially expressed genes tested by FQ-PCR were consistent with the microarray. Twelve abnormally expressed cytoskeletal genes were confirmed by RT-PCR. Expression of 11 was significantly higher in the ATN of IE patients than in controls. Gene products altered in IE, namely HSPBAP1, TRAP220, glycogen synthase kinase-3beta (GSK-3beta), and cyclin-dependent kinase 5 (CDK5), were tested by immunohistochemistry and immunoblotting. GSK-3beta and CDK5 levels were significantly higher in the ATN of IE patients. Our gene chip data are generally in agreement with the published findings on epilepsy. Thus, gene chips may serve as a screening tool to elucidate the pathophysiology of IE. Investigation of some of these newly identified genes should enhance our understanding of the molecular mechanisms of epileptogenesis.
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