Transcriptomic and electrophysiological alterations underlying phenotypic variability in SCN1A-associated febrile...

Area of Science:

• Neuroscience
• Genetics
• Cell Biology

Background:

• Febrile seizures (FS) are common childhood neurological events, but some children develop epilepsy.
• Mutations in SCN1A, a gene for a sodium channel subunit, are linked to epilepsy syndromes following FS.
• The precise mechanisms causing epilepsy development after FS remain unclear.

Purpose of the Study:

• To investigate the phenotypic variability in individuals with the same SCN1A mutation.
• To explore the cellular and molecular differences in neurons from siblings with FS, one developing epilepsy.

Main Methods:

• Utilized induced pluripotent stem cell (iPSC)-derived neurons from two siblings carrying the SCN1A c.434T>C mutation.
• Performed transcriptomic analysis to compare gene expression profiles.
• Conducted voltage-clamp recordings to assess synaptic activity.

Main Results:

• Both siblings' neurons showed downregulation of GABAergic pathway genes, consistent with SCN1A-related epilepsy.
• Neurons from the sibling with temporal lobe epilepsy (TLE) displayed additional abnormalities: altered AMPA receptor composition, modified GABA_A receptor and chloride cotransporter expression, and reduced brain-derived neurotrophic factor (BDNF).
• Synaptic activity analysis revealed impaired GABAergic and AMPA receptor function in the TLE sibling's neurons.

Conclusions:

• Combined GABAergic dysfunction, aberrant AMPA receptor signaling, and reduced BDNF contribute to epilepsy susceptibility in FS.
• These molecular differences may explain the variable development of epilepsy, such as TLE, in individuals with the same SCN1A mutation.