Abstracts

Rationale: Children who experience a seizure in the first year of life have a higher risk of autism than the general population. Evidence from rodent models has shown that experiencing seizures during sensitive periods of development produces long-term behavioral deficits, specifically disruptions in sociability and repetitive behavior. However, less is known regarding early-life seizures and another aspect of autistic-like behavior, communication. In addition, the impact of early-life seizures often stem from studies utilizing chemoconvulsants that produce a single continuous seizure, or status epilepticus. It is unknown whether the magnitude of autistic-like behavioral impairments, specifically in communicative behaviors, could be related to seizure frequency load in early periods of development.   Methods: In the present study, we evaluated the impact of different seizure frequency loads during early-life vocalization development in C57BL/6 male and female mice. For the high seizure load (HSL) paradigm, 3 flurothyl seizures were administered to mice on postnatal days (PD) 7 to 11 (15 total seizures) and ultrasonic vocalizations (USVs) were recorded on PD12. For the low seizure load (LSL) paradigm, only 3 flurothyl seizures were administered on PD10, with USVs recorded on PD12. In a separate cohort of mice that underwent the LSL paradigm, we collected hippocampal tissue for western blotting at 1hr, 24hr, on PD12 and PD15 following the final seizure on PD10 to determine whether PI3K/Akt/mTOR signaling and seizure-induced neuroinflammation could be underlying vocalization development in pups.  Results: We found that the induction of seizures across PD7 to 11 in the HSL paradigm resulted in increased average duration (p < 0.05) and cumulative duration (p < 0.05) of USVs across both sexes. Qualitative analyses indicated several call type changes, including reduced production of complex call types from males in the HSL condition (p < 0.05). In the LSL paradigm, no changes were detected in any spectral or temporal features of USVs, however, call type analyses indicated that both LSL males and females produced significant changes in call types. Western blotting analyses indicated seizure-induced increases in proteins involved in the PI3K/Akt/mTOR pathway (% total pAkt, S6) and enhanced neuroinflammation (GFAP, Iba1) at varying timepoints post-PD10 seizures.  Conclusions: This study provides evidence that experiencing a HSL, but not a LSL, early in development elicits significant changes in vocalization behavior. Additionally, we found that alterations in the mTOR signaling pathway, along with enhanced seizure-induced inflammation, could underlie these alterations. These findings suggest that seizure load early in life could play a role in the magnitude of autistic-like communicative impairments often present in individuals with epilepsy.  Funding: This work was supported by the National Institutes of Health (NIH) to Joaquin N. Lugo [Grant Number: NS088776].