Abstracts

Rationale: Dravet Syndrome (DS) is a severe childhood epileptic encephalopathy (EE) that includes seizures, ataxia, and intellectual disability with a high risk of SUDEP. Most DS patients have de novo mutations in SCN1A that result in haploinsufficiency of the voltage-gated sodium channel NaV1.1 a subunit. A small subset of DS/EE patients has inherited, homozygous loss-of-function mutations in SCN1B, encoding the voltage-gated sodium channel subunits b1 and b1B. Thus, we have proposed that Scn1b null mice model DS/EE. b1 and b1B are multifunctional proteins that signal through multiple signal transduction pathways on multiple time scales. b1 and b1B modulate sodium channel function, increase sodium channel a subunit plasma membrane expression, and direct sodium channel a subunit subcellular localization. In addition, b1 and b1B are immunoglobulin superfamily cell adhesion molecules that play roles in neuronal migration, axon-pathfinding, and fasciculation. Scn1b-null mice exhibit spontaneous behavioral seizures beginning around postnatal day (P)10, are ataxic, and die by ~P21. We have shown that Scn1b-null mice display significant developmental defects in the hippocampus and cerebellum, including abnormal neuronal migration, axonal pathfinding, and fasciculation, as early as P5. Here, we are investigating a possible role for Scn1b in the formation of synapses in the cerebellar cortex.Methods: Using immunohistochemistry techniques, we labeled GABAergic synapses in sections of cerebellar cortex.Results: We observe a significant reduction in the number of VGAT-positive GABAergic synapses on Purkinje cell somata of Scn1b-null mice at P14 (N = 6). Our ongoing work is examining the number of excitatory synapses in the cerebellar cortex using anti-VGLUT1 and anti-VGLUT2 antibodies to label those arising from parallel fibers and climbing fibers, respectively. To determine if the observed reduction in synapses is age-dependent, we are studying the Scn1b-null cerebellar cortex at earlier and later time points.Conclusions: These results will expand on the current knowledge of how b1 and b1B function in the developing brain and may provide new insights into the mechanism by which SCN1B loss-of-function leads to hyperexcitability in DS/EE patients.