PROJECT SUMMARY Dysfunction of voltage-gated sodium channels (VGSCs) is responsible for several forms of catastrophic childhood encephalopathies. Over 1000 loss-of-function mutations in the VGSC SCN1A have been identified during the last two decades and are the main cause of Dravet syndrome (DS), characterized by recurrent early- life febrile seizures (FSs), severe afebrile epilepsy, cognitive and behavioral deficits, and a 15-20% mortality rate. Mutations in the VGSC SCN8A were more recently identified in 2012, and already over 200 gain-of-function SCN8A mutations have been reported in patients with a range of clinical features including catastrophic treatment-resistant childhood epilepsy, autism, intellectual disability and developmental delay. Unfortunately, most anti-epileptic drugs (AEDs) fail to adequately treat the broad range of severe seizures and behavioral phenotypes in patients with SCN1A- and SCN8A-derived epilepsy. Thus, despite recent progress in pharmacological treatments for DS, there remains a need to develop more effective, longer lasting treatments with fewer side effects. Neuropeptides are well known in animal studies to show great promise for controlling seizures and ameliorating behavioral abnormalities; however, they do not readily cross the blood brain barrier and are rapidly metabolized when given systemically. Thus, poor brain penetrance is a critical barrier to the clinical application of these promising therapeutics. To overcome this challenge, we developed and validated an approach based on the encapsulation of neuropeptides in nanoparticles conjugated to rabies virus glycoprotein (RVG). Using this approach, we have found that intranasal delivery of nanoparticle-encapsulated oxytocin (NP- OT) greatly increases brain penetrance and the capacity of OT to confer robust and sustained increases in resistance to seizures in mouse models of SCN1A and SCN8A dysfunction. We have also extended our strategy to encapsulate neuropeptide Y (NP-NPY), and similarly observed a robust improvement in its ability to confer seizure resistance. In the proposed study, we will establish the ability of NP-OT and NP-NPY to ameliorate spontaneous seizures and behavioral abnormalities in Scn1a and Scn8a mouse mutants (Aim 1). While the role of OT in social behavior is well-studied, less is known about the mechanisms by which it modulates seizure susceptibility. Thus, we will also identify the cellular and neural circuit mechanisms that contribute to the ability of OT to increase seizure resistance in the Scn1a and Scn8a mutants (Aim 2). Our long-term goal is to develop safe and effective approaches for the brain delivery of neuropeptides for the treatment of epilepsy and other neurological disorders.