¹Tokyo Metropolitan Institute of Medical Science, Department of Psychiatry and Behavioral Sciences, Tokyo, Japan, ²Fukuoka Prefectual University, Psychology, School of Human and Social Sciences, Fukuoka, Japan, ³Tokyo Metropolitan Institute of Medical Science, Center for Basic Technology Research Director of Technology Research Division, Tokyo, Japan, ⁴Tokyo Metropolitan Institute of Medical Science, Department of Psychiatry and Bhavioral Sciences, Tokyo, Japan, ⁵Tokyo Metropolitan Institute of Medical Science, Depatment of Psychiatry and Behavioral Sciences, Tokyo, Japan

Background: The EL mouse has been considered a genetic model for human partial seizures with secondary generalization. In our previous studies, Translocator Protein 18 kDa (TSPO) in the brain of EL mice is involved in their epileptic seizures.

Aims & Objectives: In this study, we further analyzed TSPO in EL mice in comparison with their control DDY mice. In addition, abnormal behaviors such as anxiety and hyperactivity of EL mice were studied.

Method: In seizure experiments, the convulsant Ro5-4864 (i.p.), an agonist for TSPO, elicited tonic-clonic convulsions in EL mice 2.6-times more potently than in DDY mice. In contrast, PK11195 (i.v.), an antagonist for TSPO, significantly raised the seizure threshold. Binding　assay revealed a 50% higher density of [³H]Ro5-4864 binding sites in the mitochondrial fraction isolated from the cerebrum of EL mice in comparison with DDY mice. The results support the hypothesis that TSPO associated with mitochondria is involved in the pathogenesis of epileptic seizures in EL mice. Next, in behavioral experiments, we examined whether EL mice develop fear-responses using the elevated plus-maze (EPM) test. In addition, the production of fecal boli was used as an indicator of increased anxiety. EL mice, which are hyperactive by nature, made higher scores in the number of total arm entries than DDY mice. The number of fecal boli was always greater in EL mice than DDY during the EPM test. The results suggest that EL mice develop anxiety possibly as a consequence of TSPO abnormalities. Finally, we examined whether EL mice can be used as an animal model for attention-deficit hyperactivity disorder (ADHD) as well. Methylphenidate, the most widely used agent for ADHD treatment, unexpectedly increased activities of both EL and DDY mice. In contrast, fluoxetine, a selective serotonin reuptake inhibitor (SSRI), being used for some patients with ADHD, exerted anti-convulsant actions in EL mice, and appeared to normalize both hyperactive and anxiety behaviors.

Results: The results indicates that fluoxetine, but not methylphenidate, exerts both calming and anxiolytic actions in EL mice. It remains to be seen how TSPO mediates these actions of SSRI.

Discussion & Conclusions: We conclude that EL mouse may be a useful animal model for epilepsy, anxiety and hyperactivity, in which TSPO will be a promising target for drug development.