SCN8A encodes a major voltage-gated sodium channel expressed in CNS and PNS neurons.  Gain-of-function and loss-of-function mutations contribute to  human disorders, most notably Developmental and Epileptic Encephalophy (DEE). More than 600 affected individuals have been reported, with the most common  mechanism of de novo, gain-of-function mutations.  We have developed constitutive  and conditional models of gain- and loss- of function mutations in the mouse and  characterized the effects of on neuronal firing and neurological phenotypes.  Using CRE lines with cellular and developmental specificity, we have probed the effects of activating  mutant alleles in various classes of neurons in the developing and adult mouse.   Most recently, we are testing genetic therapies that reduce the expression  of gain-of-function mutant alleles.  We are comparing the effectiveness of allele specific  oligos (ASOs), viral delivery of shRNAs, and allele-specific targeting of mutant alleles  using Crispr/Cas9 in mouse models of DEE.