Research Scientist University of Washington, Washington
This abstract has been invited to present during the Better Patient Outcomes through Diversity Platform poster session
Rationale: Dravet syndrome is an intractable epilepsy caused by caused by loss-of-function mutations in SCN1A with characteristic febrile seizures beginning in infancy. Genetic DS mouse models recapitulate the core epileptic and behavioral phenotypes and work in DS mice has identified impaired inhibitory interneuron excitability, a likely cause of seizures and comorbidities such as cognitive impairment. Inhibition provides timing and control of neuronal recruitment. Hippocampal sharp-wave ripples (SWR) are required for intact learning and memory, depend on inhibitory interneurons, and are impaired in DS. Neuronal excitability, synaptic strength, and resultant brain network behavior are temperature-dependent. We hypothesize that in DS, inhibition is unable to balance temperature-related increases in hippocampal excitation impairing SWR generation, increasing internal ripple frequency, and ultimately leading to interictal spikes (IIS) and seizures. These preliminary findings report a temperature-dependent increase in internal ripple frequency and a parallel increase in the rate of IIS in DS but not wild-type (WT) mice while rate of SWR occurrence decreases with temperature in both genotypes. SWR occurrence is briefly suppressed following IIS. Methods: In vivo stereotactic fine-wire hippocampal depth electrodes were used to record local field potentials at baseline temperature and during controlled body temperature elevation to 40°C in adult DS mice and WT controls. DS N=6, WT N=4. SWR and IIS were detected offline using an in-house algorithms. Results: DS mice had a slower average internal ripple frequency at baseline (BL) temperature (< 38°C; DS 132.4 ± 2.9 Hz; WT 162.76 ± 3.28 p< 0.05, two-tailed t test), and at elevated temperatures ( > 38°C; DS 146.3 ± 4.5 Hz, WT 173.65 ± 7.28 p< 0.05, two-tailed t test). Within genotype, 6/6 DS and 2/5 WT mice showed a significant positive correlation between frequency and temperature (linear correlation test). IIS rate over time and per SWR increased with temperature in DS mice (BL: 0.0075 ±0.003 spikes/sec, 0.043 ±0.02 spikes/SWR; >38°C: 0.019 ±0.004 spikes/sec, 0.18 ±0.07 spikes/SWR). No IIS were reported in WT recordings. SWR rate decreased for both WT and DS above 38°C (WT BL 0.275 ±0.02, >38°C 0.1 ±0.02 p< 0.01, two tailed t-test; DS BL 0.22 ±0.04, >38°C 0.11 ±0.02 p< 0.05 two tailed t-test.) Conclusions: These experiments demonstrate: (1) Internal ripple frequency is controlled independent of temperature in WT while frequency increases with temperature in DS which suggests a temperature-dependent alteration in excitatory-inhibitory balance. (2) As previously observed ripples are slower in DS compared to WT at all temperatures possibly due to reduced excitability of inhibitory neurons required for pacing high frequency network oscillations. (3) IIS, which only occur in DS mice, are increasingly common with temperature and briefly suppress SWR suggesting common network elements are involved. Funding: Please list any funding that was received in support of this abstract.: This work was supported by a grant front the National Institute of Health.
