Abstracts

Absence seizures are common in patients with developmental and epileptic encephalopathies (DEEs).^1,2 The 5-hydroxytryptamine type 2C (5-HT_2C) receptor has been reported to modulate thalamocortical circuitry that is implicated in the generation of absence seizures, making 5-HT_2C a promising therapeutic target for addressing this seizure type.^3,4 Bexicaserin, a potent and highly selective 5-HT_2C receptor superagonist, is an investigational molecule currently in Phase 3 development for the treatment of seizures in patients with DEEs. We have previously shown that bexicaserin reduces absence seizures in a preclinical model of absence epilepsy.⁵ Here, we investigated the effect of bexicaserin on thalamocortical circuit activity using slice electrophysiology and evaluated the contribution of 5-HT_2C receptors to the effects of bexicaserin on absence seizures.  

Coronal brain slices containing the ventrobasal (VB) thalamus were prepared from 3-week-old Wistar rats for ex vivo whole-cell patch-clamp electrophysiological recordings of VB thalamocortical neurons. Spontaneous inhibitory postsynaptic currents (sIPSCs) and tonic currents mediated by extrasynaptic GABA_A receptors were recorded at -70 mV before and after bath application of vehicle, bexicaserin, or bexicaserin plus the selective 5-HT_2C antagonist SB242084. To determine the effect of bexicaserin on absence seizures in vivo, male Genetic Absence Epilepsy Rats from Strasbourg (GAERS) were implanted with frontoparietal cortical electrodes, and the number and duration of spike-wave discharges (SWDs) were recorded for 150 minutes following administration of vehicle, bexicaserin, SB242084, or bexicaserin plus SB242084.

Bexicaserin significantly reduced sIPSC frequency and amplitude, as well as the amplitude of the extrasynaptic tonic current (P<