The aim of this investigation is to examine how SCN1A loss-of-function mutations (encoding a voltage-gated sodium channel) lead to abnormal network dynamics resulting in epileptic seizures, as reported in patients with Dravet syndrome.

Question 1 (Q1): How does a loss-of-function sodium channel mutation lead to a paradoxical increase in neuronal excitation?
Hypothesis 1: The mutation preferentially leads to decreased excitability of inhibitory neurons causing aberrant disinhibition of excitatory neurons.

Question 2 (Q2): How do different SCN1A mutations, causing divergent biophysical abnormalities in patients, lead to a common clinical phenotype?
Hypothesis 2: Mutations along different regions of the SCN1A gene differentially alter sodium channel gating dynamics, which downstream converge to cause network hyper-excitability.

Question 3 (Q3): How do SCN1A mutations lead to abnormal network dynamics, as measured with light sheet fluorescence microscopy (LSFM) and electro-encephalogram (EEG)?
Hypothesis 3: SCN1A mutations result in common abnormalities in neuronal coupling across LSFM and EEG.