Abstract:
Human brain VGSCs are related to the action potential of the neuron. Functional
changes happen in human VGSCs can induce neuronal hyperexcitability and result in
seizures. SCN2A which codes for the hNav1.2 channel, is one important gene associated with neonatal-onset epilepsy. Neonatal-onset epilepsy is defined as an onset within four weeks after birth. A severe neonatal-onset epilepsy can cause permanent developmental regression and resistance to AEDs treatment.
In this dissertation, both A1659V and I1640M mutations of SCN2A associated with
neonatal-onset epilepsy were functionally analyzed using electrophysiology technique.
Either the WT or the mutation, with the hβ1 and hβ2, were co-expressed in tsA201 cells
for functional studies. Both mutations shifted in depolarization direction in fast
inactivation and speed up recovery from it. Moreover, A1659V mutation presented
increasing persistent INa and slower fast inactivation. All these functional changes
indicated clear GOF effects. These functional consequences predict an increase in
channel availability for action potentials, a shorter refractory period and more inward
sodium current that can depolarize the neuronal cell membrane. The detected changes
can therefore well explain a neuronal hyperexcitability which can result in epileptic
seizures.
Further studies need to be performed using neurons and neuronal networks to
understand neuronal hyperexcitability. First consequences for treatment result from
such studies since GOF mutations in SCN2A can be well treated by Na+ channel
blockers. However, further drugs are needed, since not all patients respond and some
have severe side effects.
epilepsy