Introduction: Temporal lobe epilepsy (TLE) is clinically relevant due to its severity and the high percentage of patients resistant to available medications. In the search for more refined and technically and ethically appropriate animal models, the chemogenetic tool called DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) has opened new frontiers in the study of drugs with clinical applications. Therefore, the aim of this study is to develop an animal model of DREADD-induced epilepsy in rodents. Methodology: Phase I: Nine animals, divided into 3 groups (n = 3), were intracerebrally infused with a viral vector for receptor expression in the area tempestas (namely: GiDREADD; rM3D; and hM3D). During testing, the animals received two weekly administrations (1 and 5 mg/kg) of clozapine N-oxide (CNO) for 4 weeks after surgery. Phase II: Eight animals were intracerebrally infused with the viral vector (pAAV-hDix-GiDREADD-dTomato-Fishell-5). In behavioral tests, the animals underwent two tests where the dose of clozapine N-oxide (CNO) was randomized (5 or 10 mg/kg) and one control test. At the end of the experiment, euthanasia and histological analysis were performed. Conclusion: The pAAV-hDix-GiDREADD-dTomato-Fishell-5 vector was able to be bilaterally expressed in the area tempestas, and its activation induced seizures in the experimental subjects, particularly at doses of 5 and 10 mg/kg. The latencies to seizure onset were similar for both CNO doses. To the best of our knowledge based on the available literature, this is the first report of seizure induction via chemogenetics. The project phases were approved by the Animal Use Ethics Committee (CEUA) of the University of Brasília under protocols No. 23106.151489/2022-18 and No. 23106.128947/2023-04.
Author Contributions
Conceptualization, G.F.O., M.C.A.-C., M.M., P.A.F. and R.S.M.; methodology, G.F.O., M.C.A.-C. and R.S.M.; software, M.C.A.-C., A.B. and G.F.O.; validation, G.F.O., M.C.A.-C., M.M., P.A.F. and R.S.M.; formal analysis, G.F.O., M.C.A.-C. and R.S.M.; investigation, G.F.O. and M.C.A.-C.; resources, M.C.A.-C., A.B., M.M., P.A.F. and R.S.M.; data curation, G.F.O. and M.C.A.-C.; writing—original draft preparation, G.F.O. and M.C.A.-C.; writing—review and editing, G.F.O. and M.C.A.-C.; visualization, G.F.O. and M.C.A.-C.; supervision, R.S.M.; project administration, G.F.O., M.C.A.-C., M.M., A.B., P.A.F. and R.S.M.; funding acquisition, M.C.A.-C., A.B., M.M., P.A.F. and R.S.M. All authors have read and agreed to the published version of the manuscript.
Funding
This research was funded by Fapdf process no 00193-00000725/2021-84.
Institutional Review Board Statement
The handling of experimental animals follows the Ethical Principles in Animal Experimentation, the National Council for Animal Experimentation Control (CONCEA), and the Arouca Law (Law 11.794/2008). The phases of the project developed so far have been approved by the Animal Use Ethics Committee (CEUA) of the University of Brasília under No. 23106.151489/2022-18 and No. 23106.128947/2023-04.
Informed Consent Statement
Not applicable.
Data Availability Statement
The data presented in this study are available upon request from the corresponding author.
Conflicts of Interest
The authors declare no conflict of interest.
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