Abstracts

This abstract has been invited to present during the Basic Mechanisms platform session

Rationale: Epileptic encephalopathies (EE) of infancy and childhood constitute a large, heterogeneous group of severe intractable epilepsies characterized by several seizure types, frequent epileptiform activity in the EEG, and developmental slowing and/or regression. Previous work has shown that a genetic mouse model of EE, i.e., the Ank3-1b-/- mice exhibited reduced PV excitabilities and synchrony, which led to a highly penetrant EE phenotype, and sudden death at a young age. However, little is known about how sensory information is processed in these animals.

Methods: We used a combination of approaches including in vivo electrophysiology recordings from  head-fixed freely moving and anesthetized animals,  behavior tests and EEG recordings to examine the the sensori-processing deficits and circuit mechanisms.   

Results: To understand the properties of the spontaneous chronic epilepsy in Ank3-1b-/- mice, we have conducted pilot EEG recordings simultaneously with non-invasive behavior monitoring. Our data show that stereotyped chronic epilepsy is present in 10/10 Ank3-1b-/- mice. The core features of spontaneous epilepsy in Ank3-1b-/- demonstrated clear signs of EE: (1) SWD seizures were recorded from Ank3-1b-/- mice in as early as 12 postnatal days; (2) at one month of age, these mice exhibited neocortex dominant continuous spike-waves during slow-wave sleep (CSWS), which resembles the human electrical status epilepticus during slow-wave sleep (ESES); and (3) the pattern of CSWS discharges progressed steadily throughout the adolescent period with seizures becoming more intense, larger in amplitude, and more diverse (generalized, focal and tonic, and myoclonic).Thus these data establish Ank3-1b-/- mice has the face and construct validity as a mouse genetic model of EE. In the open field (OF), and novel object recognition (NOR) tests, Ank3-1b-/- mice exhibited heightened stress levels and performed the NOR significantly poorly vs. age matched controls, indicating cognitive deficits. To understand the circuit mechanisms underlying the sensory-processing deficits, we performed linear electrode array recordings from S1 barrel field in head-fixed awake and fully moving animals while these animals receive somatosensory stimulations (air-puff to the whiskers). Whisker evoked local field potentials (LFPs) were further processed to generate current-source-density (CSD) and single units (SU). We found that although both WT and Ank3-1b-/- mice exhibited clear single and repetitive air-puff evoked SU patterns;   the single air-puff evoked AVREC value of the CSD were significantly larger in Ank3-1b-/- mice, and that there are concomitant changes in the layer-specific distribution of putative excitatory vs. inhibitory single unit activities evoked by the air-puff stimulations.  

Conclusions: Our data thus provide a clear demonstration of sensory and cognitive deficits in a mouse genetic model of EE, and further elucidates the cortical circuit and cellular deficits in the somatosensory cortex. Our data pinpoint to the excitability of parvalbumin interneurons, as a key substrate linking sensory endophenotype and EE.   

Funding: NINDS