Authors :
Presenting Author: Sydney Pell, BS – Baylor University
Katherine Blandin, PhD – Baylor University
Taylor Bradish, M.S. – Baylor University
Madison Wallis, BS – Baylor University
Colton Kelley, BS – University of California Davis
Luke Hammett, BS – Baylor University
Josh Thayil, -- – Baylor University
Ashley Smelley, BS – Baylor University
Gautham Chelliah, BS – Baylor University
David Narvaiz, PhD – University of Texas San Antonio
Linay Burge, BS – Baylor University
Chloe Lau, BS – Baylor University
Kendall Lally, BS – Baylor University
Leighton Douglas, BS – Baylor University
Joaquin Lugo, PhD – Baylor University
Rationale:
Epilepsy has a high prevalence during childhood and increases the risk of developing other cognitive and behavioral comorbidities. Seizures increase the release of proinflammatory cytokines, which increase excitability and the likelihood of additional seizures. Dysregulation in the mechanistic target of rapamycin (mTOR) pathway have been found in epilepsy syndromes and is common in many disorders associated with autism spectrum disorder. Rapamycin is an inhibitor of mTOR protein kinase, while minocycline is an anti-inflammatory drug, and both are effective in treating certain types of epilepsy. The present study examined the role of PI3k/Akt/mTOR pathway activity and neuroinflammation in the development of autistic-like behaviors following seizures in the neonatal period.
Methods:
We used C57BL/6J mice to investigate the role of neonatal seizures in the development of autistic-like behaviors. Neonatal seizures were induced on postnatal day (PD) 10 via an intraperitoneal injection of 1.5 mg/kg kainic acid. Three hours later, the mice were treated with either saline (S), minocycline (M), rapamycin (R), or both minocycline and rapamycin (M/R). At two to three months of age the mice were run through a battery of behavioral assays to assess autistic-like behaviors. The assays ran include open field, elevated plus maze, nose poke, social chamber, marble burying, and delayed fear conditioning to assess locomotor activity, anxiety, social behavior, repetitive behaviors, and memory.
Results:
Analysis of the data from open field and elevated plus maze shows that seizures did not influence locomotor activity or anxiety behaviors. However, the R and M/R treatment group traveled a significantly shorter total distance and distance in both the center and surround areas than the M and S groups in the open field. The R group went into the closed arms less frequently than the S group in elevated plus maze. The M/R mice had more repeated nose pokes than the S mice, and in the marble burying assay, seizures resulted in a decrease in marbles buried compared to controls. In social chamber, treatment with R and M/R resulted in a decrease in cup and chamber frequency compared to the S and M groups. Finally, in delayed fear conditioning, seizures resulted in an increase in freezing behavior in both context and tone conditions. Treatment with R and M/R also resulted in an increase in freezing behavior for context conditions alone.
Conclusions:
We found changes in overall activity, with the mice treated with R and M/R having decreased activity in the open field and social chamber assays. We did not see an effect of seizures or treatment on repetitive behaviors or anxiety-like behaviors in the nose poke, marble burying, and elevated plus maze. We saw that both seizures and treatment with R and M/R increased fear memory in the delayed fear conditioning tasks. Overall, we believe that our results will give us a more comprehensive view of the developmental profile of early-life seizures and autistic-like behaviors, and the beneficial effects of rapamycin and minocycline.
Funding: NIH Grant R15S088776