Abstracts

Rationale: Shank3 is one of the core scaffolding proteins encoding for macromolecular complexes and has been linked with several neuropsychiatric conditions including autism spectrum disorder (ASD). The increased risk of seizures and incidence of epilepsy in individuals with ASD has long been known. Alterations in the excitatory/inhibitory balance contribute to seizure phenotypes observed across several rodent models. The severity of epilepsy in autism-related Shank3 deficiency has not been studied previously. Here for the first time, we test the susceptibility to induced seizures in Shank3B knockouts.Methods: Shank3B knockout (n=6) and wild-type control (n=7) mice at 6-7 weeks age were intraperitoneally implanted with wireless telemetry transmitters to record continuous video EEG, core body temperature, and locomotor activity. After acquiring a healthy baseline, mice were challenged with pentylenetetrazole (PTZ), a GABAA receptor antagonist. Seizure thresholds were assessed in both groups by video-EEG using automated seizure detection and spectral analysis software, and confirmed by visual inspection.Results: Shank3B knockout mice were relatively protected from PTZ-induced seizures. Upon PTZ administration, compared to wild-type controls, Shank3B knockout mice had reduced number of interictal spikes on the EEG (p=0.003), a significantly longer latency (p<0.0001) and reduced frequency (p=0.007) of myoclonic seizures. Shank3B also exhibited increased power in the gamma (30-80 Hz) frequency band during pre-PTZ baseline (p=0.007). This work is funded by Autism Speaks and is a part of the Pre-Clinical Autism Consortium for Therapeutics (PACT).Conclusions: We demonstrate that PTZ-induced seizure threshold is increased in Shank3B knockout mice that are more resistant from such seizures than controls. The increase in gamma power on EEG suggests a plausible increase in GABAergic reserve in this phenotype that may account for the seizure resistance. Our results suggest Shank3-related biology as a novel antiepileptic therapy target.