Abstracts

Rationale: Dravet syndrome (DS) is among the most severe and pharmacoresistant forms of childhood epilepsies (Caraballo & Fejerman 2006, Dravet 2011). The first symptoms of the disease usually manifest at about 6 months of age with the onset of febrile seizures (Ragona et al 2010). Seizure incidence often increases in both frequency and severity, and progress into non-febrile seizures by early childhood. In addition to having a high mortality rate of about 20%, Dravet patients suffer from behavioral comorbidities that include social and cognitive dysfunctions (Dravet 2011, Li et al 2011, Wolff et al 2006). Methods: Using a transgenic DS mouse model with a knock-in mutation in the SCN1A gene that encodes the voltage-gated sodium channel NaV1.1 (Ogiwara et al 2007), we tested a novel drug strategy. We performed sub-chronic adenosine A1 receptor agonist treatment during early postnatal development and tested effects of this treatment on the long-term survival rate, cognitive and behavioral comorbidities, and astroglial network structure in the hippocampus using FarSight (Kulkarni et al 2015), a 3D image analysis toolkit developed at UH. Previous work in the laboratory showed that this treatment was effective at reducing hyperthermia-induced seizures in vivo. Results: On a cellular level, we discovered that SCN1A mutation increases astrogliosis and alters astrocyte morphology. In vivo, prolonged early treatment with A1R agonist CPA (N-6-cyclopentyladenosine) increased viability rates from 33% to 82% (WT/saline n=24, SCN1A(+/-)/saline n=26, WT/CPA n=20, SCN1A(+/-)/CPA n=27), improved sociability (WT/saline n=22, SCN1A(+/-)/saline n=12, WT/CPA n=16, SCN1A(+/-)/CPA n=11; p < 0.05), and restored long-term hippocampal-based memory (WT/saline n=15, SCN1A(+/-)/saline n=10, WT/CPA n=14, SCN1A(+/-)/CPA n=10; p < 0.05) in the DS mice. Preliminary data analysis also indicates that this A1R treatment prevents astrogliosis and glial morphological dysfunctions (n=8 animals/group with 3 tissue slices/animal; p < 0.05) in the SCN1A mouse model of DS. Conclusions: Our studies show that early postnatal treatment with A1R agonist CPA is beneficial for survival, comorbidity outcomes, and has the ability to restructure glial networks in the hippocampus. Further translational studies will determine if A1R agonist could become a viable therapy option for patients with DS. Funding: This research is supported by Dravet Syndrome Foundation (J), University of Houston GEAR (J), University of Houston SURF and PURS (CR), Houston Livestock Show and Rodeo (LM), and University of Houston Biology of Behavior Institute (LM and FG).