Serotonergic modulation as a therapy for Dravet's Syndrome

Dravet's syndrome is a rare, severe, genetic epileptic encephalopathy. Most cases of Dravet's syndrome are caused by a mutation in the SCN1A gene. This gene codes for a sodium channel, voltage gated type 1 alpha subunit. Most of these mutated genes are expressed in GABAergic neurons; hence, GABAergic neurotransmission is compromised. GABA is a neurotransmitter with vast inhibitory functions. As such, seizurelike locomotor behavior and epileptiform brain activity are signs of Dravet's syndrome. In humans, the presence of one mutant allele is sufficient enough for the display of the mutant phenotype but in zebrafish, the common model organism for studying neural networks and disorders, the mutant phenotype is only observed in larvae that have two copies of the mutant allele. Though GABAergic neurotransmission has been found to be most directly affected by the mutations underlying Dravet's syndrome, scientists have explored the potential of other neurotransmitters rescuing the phenotype, relieving mutant zebrafish larvae of epileptic seizures. One of the neurotransmitters that has shown some promise is serotonin (5-hydroxytryptamine). It's been revealed that increasing serotonin levels can reduce epileptic locomotor and brain activity. The drug fenafluramine was identified to be capable of targeting serotonin receptor subtypes, acting as an agonist for those subtypes and allowing serotonergic neurotransmission. However, this drug does not restore the sodium channels that are absent in GABAergic neurons. While this drug is effective at targeting the right subtypes, it does have some comorbidities. It happens to target the serotonin-2B receptor subtype, which leads to cardiac valve hypertrophy. Fenafluramine's off-target activity has made it unsuitable for use in treating Dravet's syndrome.