Abstracts

Rationale: Epilepsy shares a high comorbidity with autism spectrum disorder (ASD). A signaling cascade that plays a crucial role in the development of both epilepsy and autism is the PI3K/AKT/mTOR pathway. A mouse model that illustrates this connection is the neuronal subset specific (NS) Pten knockout model which exhibits hyperactivity of mTOR. Although communication deficits are an important component of epilepsy and ASD, few studies have assessed communicative behaviors in NS-Pten knockout animals. Therefore, the present study sought to characterize communicative behaviors in NS-Pten wildtype and knockout pup and adult mice.  Methods: Neonatal vocalizations were elicited from males and females on postnatal days 8 and 11 by separating the pups from their mother (maternal isolation paradigm). Vocalizations were individually recorded for a 2-minute duration, with the pups being placed back into the home cage after the testing had concluded. Adult vocalizations were elicited from 7-week-old males via the female urine induced vocalization paradigm, wherein urine was collected from age matched females that were in estrus and then pipetted into the center of a chamber lined with paper. Male mice were placed in the chamber and recorded for a 5-minute duration. The communicative behavior known as scent marking was also assessed by spraying the paper in the chamber with ninhydrin, then tallying up the quantity of scent marks made.  Results:  In pups, we found that knockout mice emitted fewer vocalizations for both sexes, (p < .01). Knockout males had calls of a shorter duration (p < .001) and lower peak amplitude on day 8 (p < .001), while showing a shorter duration (p < .001), lower peak amplitude (p < .001), higher peak frequency (p < .001), and fundamental frequency (p < .001) on day 11. Knockout females vocalized at a lower peak amplitude (p< .001), fundamental frequency (p < .001), and a higher peak frequency (p < .001), on day 8, while showing a shorter duration (p < .001), higher peak frequency (p < .001), and fundamental frequency (p < .001), on day 11. Spectrographic analyses also revealed significant differences in call type utilization for both genotypes and sexes (p< .05). Adult NS-Pten knockout mice did not display a difference in call quantity or scent marking behavior (p > .05). Knockout mice did display a decreased peak frequency (p < .05), duration (p < .05), and an increased peak amplitude (p < .05), with no difference in the fundamental frequency of the vocalizations (p > .05). Additionally, adult knockout mice utilized different types of calls than wildtype mice (p < .05).  Conclusions: This study suggests that hyperactivity of mTOR results in both quantitative and qualitative changes in vocalizations for both pup and adult NS-Pten knockout mice, further indicating that dysregulated vocalizations may be a behavioral biomarker of an epileptic and an autistic phenotype throughout the lifespan. Overall, our results contribute to the literature and will hopefully aid in the development of effective treatment options for the communication deficits in epileptic and autistic patients.  Funding: Funding for this work was supported by an NIH Grant R15S088776.