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Epileptic spasms in infancy: Transferring rat prenatal betamethasone-postnatal NMDA model to mice
Tamar Chachua1, Chian-Ru Chern1, Jana Velíšková2
1Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY, USA.
Abstract:
Epileptic spasms during infancy represent a devastating and refractory epilepsy syndrome. To advance studies on mechanisms and treatment using available mouse mutant models, we transferred our validated rat model of epileptic spasms to mice. Initially, we determined sensitivity of C57BL/6J mice to various doses (12-20 mg/kg) of NMDA on postnatal day 11 (P11) and P15. We primed mice with different doses of betamethasone (0.4-2.0 mg/kg) prenatally on gestational day (G)14 or G12 and tested spasms on P11. We also tested 2 different ACTH treatment paradigms (0.3 or 1.0 mg/kg) in prenatally primed as well as naïve mice. Data show that spasms in P11 mice, can be induced with the highest yield after 12 mg/kg dose of NMDA. Prenatal priming on G14 did not modify response to NMDA or sensitize spasms to ACTH. The betamethasone priming on G12 resulted in an increase in the number of NMDA-triggered spasms. Data indicate that the model transfer from rats to mice is non-linear and differences in prenatal brain development, metabolic rates, as well as sensitivity to convulsant drugs have to be considered.
Insights
Transferring an epileptic spasms rat model to mice revealed key differences. Prenatal betamethasone priming on gestational day 12 increased NMDA-triggered spasms in infant mice, suggesting non-linear model translation.
Area of Science:
- Neuroscience
- Developmental Neuroscience
- Epilepsy Research
Background:
- Infantile epileptic spasms are a severe, treatment-resistant epilepsy.
- Mouse models are crucial for studying epilepsy mechanisms and treatments.
- Previous research established a validated rat model for epileptic spasms.
Purpose of the Study:
- To adapt a validated rat model of epileptic spasms to mice.
- To investigate the effects of prenatal betamethasone and ACTH treatments on induced spasms in mice.
- To understand the non-linear translation of epilepsy models between species.
Main Methods:
- Determined NMDA sensitivity in C57BL/6J mice on postnatal days 11 and 15.
- Administered prenatal betamethasone on gestational days 12 or 14.
- Tested ACTH treatment paradigms in naive and prenatally primed mice.
Main Results:
- The highest yield of spasms in P11 mice was induced by a 12 mg/kg NMDA dose.
- Prenatal priming on G14 did not alter NMDA response or ACTH sensitization.
- Betamethasone priming on G12 increased the number of NMDA-triggered spasms.
Conclusions:
- Transferring the epileptic spasms model from rats to mice is non-linear.
- Prenatal brain development, metabolic rates, and drug sensitivity vary between species.
- Careful consideration of these differences is necessary for successful model translation.
