Dravet’s syndrome (DS) is a severe genetic epilepsy that begins in infancy and is characterized by temperature-sensitive, drug-resistant seizures, along with cognitive and motor impairments. Two FDA-approved treatments, fenfluramine (FA) and cannabidiol (CBD), have shown efficacy in reducing seizure frequency, though their mechanisms of action remain largely unknown. FA is thought to act through serotonin receptor (5HTR) subtypes 1, 2, and 4. Among these, 5HTR1s are G-protein coupled receptors (GPCRs) that signal via Gi proteins, releasing Gβγ dimers that activate G-protein gated inwardly rectifying potassium (GIRK) channels. GIRK activation hyperpolarizes neurons, reducing excitability. GIRK channels have two gating sites: one at the membrane and one in the cytosol. Gβγ and the small molecule GAT1508 couple to the two channel gates allosterically and distinctly such that when they are co-applied they produce synergistic GIRK activation. Given GIRK’s role in regulating neuronal excitability, its activation has shown promising antiepileptic effects. We hypothesize that FA activates GIRK channels via Gβγ signaling downstream of 5HTR1, reducing neuronal excitability. In hippocampal CA1 brain slices, using extracellular field potential (EFP) recordings, we have shown that FA reduces high potassium-induced epilepsy-like activity. To test whether 5HTR1 subtypes are involved in the FA reduction of epileptiform activity in our model, we use specific 5HTR1 inhibitors to identify the specific subtypes through which FA may exert its effect by signaling to GIRK channels. Lastly, we are testing for synergism between GAT1508 and the appropriate 5HT1R suggested by the inhibitor results. We aim to proceed to test the efficacy of FA and its synergy with GAT1508 in a DS epilepsy mouse model in which seizures are temperature-induced. This work will clarify FA’s mechanism of action and explore the therapeutic potential of GIRK-targeting treatments for drug-resistant epilepsy.
Rivera et al. (Sun,) studied this question.