Impact of neuroinflammatory and mTOR signaling inhibition following flurothyl seizures on the acute development of autistic-like behavior in C57BL/6 mice.


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Epilepsy is a common neurological disorder, with individuals having an increased susceptibility of seizures in the first few years of life. Children with epilepsy are at risk of developing a multitude of cognitive and behavioral comorbidities throughout development. In addition, approximately one third of individuals with epilepsy are resistant to anti-seizure drugs, emphasizing the need for therapeutics that extend beyond manipulation of neuronal transmission and target alternative mechanisms. The present study examined the role of PI3K/Akt/mTOR pathway activity and neuroinflammatory signaling in the development of autistic-like behavior following seizures in the neonatal period. Male and female C57BL/6 mice were administered 3 flurothyl seizures on postnatal (PD) 10, followed by administration of minocycline, the mTOR inhibitor rapamycin, or a combined treatment of both therapeutics. On PD12, isolation-induced ultrasonic vocalizations (USVs) of mice were examined to determine the impact of seizures and treatment on communicative behaviors, a component of the autistic-like phenotype. Hippocampal tissue was collected on PD12 to examine proinflammatory cytokine expression with qRT-PCR, along with western blotting to examine mTOR protein expression and astrocyte and microglial reactivity. Seizures on PD10 increased the quantity of USVs in female mice and reduced the amount of complex call types emitted in males compared to controls. Inhibition of mTOR with rapamycin significantly reduced the quantity and duration of USVs in both sexes. Changes in USVs were associated with increases in mTOR activity and astrocyte reactivity in male mice, however, three PD10 seizures did not result in enhanced proinflammatory cytokine expression in either sex. Rapamycin treatment significantly reduced % total pS6(235,236) and % total pS6(240,244) expression on PD12, however, minocycline did not impact any of the examined proteins. These findings emphasize the importance of differences that may exist across preclinical seizure models, as three flurothyl seizures did not induce as drastic of changes in mTOR activity or inflammation as observed in other models. Early-life seizures can have a profound impact on the developing brain, and thus it is critical to continue investigating potential therapeutics that target the underlying pathology of seizures and could prevent the development of cognitive and behavioral comorbidities.



Epilepsy. Autism. Ultrasonic vocalizations. Early-life seizures. Cell signaling. Cytokines.