UC Irvine

The number of mutations in the voltage-gated sodium channel Nav1.1, encoded by SCN1A, that have been associated with genetic epilepsy is extremely high compared to the other sodium channel genes. The crucial function of the voltage-gated sodium channels in the central nervous system (CNS) is to regulate the influx of sodium or sodium current into the neurons. Sodium currents are required for the generation and propagation of action potentials. Subsequently the action potentials cause the release of neurotransmitters that allow the communication and synchronization among neurons in a circuit. Most of the previous mouse models of Scn1a sodium channel mutations result in loss-of-function of sodium currents and decrease of excitability of interneurons. In this study, I investigate the mechanism by which a novel SCN1A mutation, D1886Y, causes epilepsy in a mouse model. Chapter 1 examines the activation, inactivation and dynamics of sodium currents in parvalbumin-expressing (PV+) interneurons from the hippocampus. The Snc1a-D1866Y mutation in these neurons resulted in gain-of-function of sodium current. Chapter 2 investigates how the Snc1a-D1866Y mutation affects the excitability of excitatory and inhibitory neurons to generate action potentials. In PV+ interneurons, the mutation reduced the excitability to fire action potentials. A reduction in action potential firing was also detected in pyramidal neurons, but to a lesser degree. Chapter 3 examines the seizure susceptibility in vivo and in the hippocampal circuit of mice expressing the Snc1a-D1866Y mutation. Our findings suggest the existence of different molecular mechanisms for how Scn1a mutations cause epilepsy. Identification of the molecular mechanisms that lead to epilepsy is crucial for the development of new anti-epileptic drugs.