Authors :
Presenting Author: Amanda McGann, BS – Cincinnati Children's Hospital Medical Center
Grace Westerkamp, CRC – Department of Neurology – Cincinnati Children's Hospital Medical Center; Alisha Chalasani, N/A – Cincinnati Children's Hospital Medical Center; Cole Danzer, N/A – Department of Neurology – Cincinnati Children's Hospital Medical Center; Ernest Pedapati, MD – Division of Child Psychiatry – Cincinnati Children's Hospital Medical Center; Paul Horn, PhD – Department of Neurology – Cincinnati Children's Hospital Medical Center; Durgesh Tiwari, PhD – Department of Neurology – Cincinnati Children's Hospital Medical Center; Steve Danzer, PhD – Department of Anesthesia – Cincinnati Children's Hospital Medical Center; Christina Gross, PhD – Department of Neurology – Cincinnati Children's Hospital Medical Center
Rationale:
Epilepsy is often caused by an initial brain insult that is followed by epileptogenesis and finally the development of spontaneous recurrent seizures. The details underlying epileptogenesis remain largely unknown. MicroRNAs regulate mRNA translation and stability and are often altered in epilepsy. Antagonism of a specific miRNA, miR-324-5p, before brain insult and in a model of chronic epilepsy has been shown to decrease seizure susceptibility and frequency. Here we tested the hypothesis that antagonism of miR-324-5p inhibits epileptogenesis following a brain insult. Methods:
We used the intrahippocampal kainic acid (IHpKa) model to induce status epilepticus and initiate epileptogenesis in 43 wild type male mice aged six to eight weeks. Twenty-four hours after kainic acid injection, we administered a miR-324-5p (21 mice) or scrambled control (22 mice) antagomir intracerebroventricularly and implanted cortical surface electrodes for EEG monitoring. EEG data was collected for 28 days and analyzed for seizure frequency and duration. In addition, we analyzed interictal spike activity and EEG power at early (days 7-9 post-Ka) and later (days 25-27 post-Ka) stages of the disease progression. Mouse brain tissue was collected for assessment of dentate granule cell dispersion and CA1 cell death.
Results:
IHpKa reliably initiated epileptogenesis. Histological analysis showed that IHpKa caused hippocampal damage characteristic of the model in the majority of mice and that the extent of the injury did not vary based on treatment. EEG analyses showed that antagomir treatment did not affect latency, frequency, or duration of spontaneous recurrent seizures or frequency of interictal spikes or spike trains. Antagomir treatment did, however, alter EEG power of specific frequency bands over time with significant interactions between time and treatment for the absolute power of select frequency bands, including delta, theta, alpha, beta, and gamma 1 bands. Conclusions:
Overall, our results suggest that while miR324-5p inhibition does not inhibit the development of spontaneous seizures within the first four weeks after status epilepticus, it may change overall brain excitability, which could affect seizures and related brain function at later stages of the disease. Funding:
1R01NS092705, 1R01NS107453, R21NS126740