Abstracts

Rationale: A common mechanistic link is believed to exist between autism spectrum disorders (ASD) and epilepsy because ~30% of individuals with ASD also have epilepsy and ~75% exhibit EEG abnormalities. Conversely, many patients with epilepsy have one or more associated autistic features. However, the underlying pathophysiology of the high co-morbidity between ASD and epilepsy remains obscure. This is in part due to the absence of clinically relevant animal models that concurrently exhibit the hallmark features of both conditions. Methods: To develop a co-morbid model of ASD and epilepsy, we utilized inbred BTBR T+ Itpr3tf/J (BTBR) mice that exhibit all three core behavioral characteristics of ASD (i.e., impaired social interactions, unusual vocalizations and repetitive stereotyped behaviors). We exposed BTBR mice to an early postnatal immune challenge, which has been shown to increase later brain excitability in other rodent models. Both groups of male and female mice received a lipopolysaccharide (LPS) injection (100 µg/kg, i.p.) or equivolume saline on postnatal day (P) 7. LPS and controls were from the same litter to minimize the effects of maternal care. Mice from a minimum of four litters constituted each experimental group. At P60, we tested seizure susceptibility by administering 1% pentylenetetrazol (PTZ) via tail-vein infusion to induce tonic-clonic seizure activity. Seizure susceptibility was calculated as the quantity of PTZ per kg of body weight required to evoke tonic-clonic seizures. To determine if spontaneous epileptiform activity was present, we surgically implanted a bipolar electrode in the dorsal hippocampus of adult BTBR mice and recorded video-EEG data over a continuous 4-week period with wireless telemetry. We also assessed whether a postnatal LPS treatment results in an ASD phenotype in adult BTBR mice. To assess ASD characteristics, we monitored three-chamber social interactions, recorded ultrasonic vocalizations, and quantified the time spent performing repetitive stereotyped behaviors such as inch-worming and self-grooming. Results: Our data indicate that early LPS exposure enhances seizure susceptibility in the BTBR model of ASD. Additionally, preliminary review of continuous video-EEG data indicates the occurrence of episodic, generalized, myoclonic jerks that are time-locked to an electrographic discharge. These electroclinical seizures appear to be more frequent in BTBR mice that received postnatal LPS treatment. Lastly, the ASD behavioral abnormalities are conserved in adult BTBR mice that received a postnatal LPS treatment compared to controls. Conclusions: These data suggest that a single postnatal immune challenge can increase brain excitability in adult BTBR mice. Future research will be directed at further characterization of this novel animal model that has a co-morbid presentation of ASD and electroclinical seizures. If successful, this model may prove to be a useful tool for elucidation of the molecular mechanisms responsible for the concurrent pathogenesis of ASD and epilepsy.