Dissecting the functional interaction between Scn1a and Scn3a genes in a therapeutic perspective for Dravet Syndrome

Dravet Syndrome (DS) is caused by genetic mutations in the SCN1A gene that encodes one of the voltage-gated sodium channel subunits known as Nav1.1, primarily expressed in inhibitory interneurons. While other channels with similar functions to Nav1.1 exist in the brain, each channel is specifically involved in the electrical activity of particular neuron types and/or specific stages of brain development.

Nav1.1 expression significantly increases after birth in both humans and mice, while Nav1.3 is abundant during prenatal brain development and decreases postnatally. This suggests that Nav1.3 might compensate for Nav1.1 function before birth. This hypothesis aligns with the onset of DS symptoms, which typically occur in the first year of life when Nav1.3 expression is likely diminished and the reduced functionality of Nav1.1 channels becomes evident.

In this project, we aim to elucidate the functional relationship between these two channels. We will investigate the developmental expression patterns of Nav1.1 and Nav1.3 and explore the potential for compensatory mechanisms between them. Additionally, we will examine the impact of premature postnatal Scn3a downregulation on the characteristic Dravet phenotype in a mouse model of the disease.

Understanding these compensatory mechanisms could lead to novel therapeutic approaches for DS, potentially involving the postnatal maintenance of Nav1.3 to mitigate the effects of Nav1.1 reduced functionality.