Abstracts

Rationale: Serotonin has a well-established capacity to suppress seizures. This is supported by preclinical research and human studies that show increasing serotonin signaling through drugs like SSRIs and fenfluramine reduces seizure burden. Recent advances in serotonin-based therapies have shown promise as epilepsy treatments, including the approval of fenfluramine for Dravet syndrome (DS); however, broad clinical use of these therapies is limited due to side effects and an incomplete understanding of the underlying therapeutic mechanisms. This project seeks to determine how serotonin regulates circuit excitability to suppress seizures, with the long-term goal of developing safer and more selective serotonin-based therapies for epilepsy. We hypothesized that serotonin modulation is important for maintaining an optimal balance of excitation and inhibition in the anterior thalamus, a key brain region involved in seizure propagation.

Methods: To test this hypothesis, we measured how serotonin modulated excitatory drive and feed-forward inhibition in the thalamus by simultaneously activating serotonergic and glutamatergic inputs in 4-week-old wild-type mice and a NaV1.1 haploinsufficient mouse model of DS. DS mice were crossed with mice expressing channelrhodopsin (ChR2-YFP) specifically in serotonergic neurons in a cre-dependent manner. Ex vivo electrophysiology and optogenetics were performed in acute brain slices to determine how serotonin release impacted excitatory and inhibitory neuron excitability and synaptic transmission.

Results: We found that serotonin modulation reduces glutamate-induced spike firing in excitatory neurons of the anterior thalamus and enhanced spiking in inhibitory neurons of the reticular thalamus. The opposing effects of serotonin on these two cell populations is, at least in part, due to serotonin depolarizing the resting membrane potential of reticular thalamus neurons, which provide feed-forward inhibition to the anterior thalamus. Serotonin also enhanced synaptic release from reticular thalamus terminals in the anterior thalamus. We further showed that the effect of serotonin on excitatory drive and feed-forward inhibition to the anterior thalamus is reduced in DS mice.

Conclusions:

Thus, the overall effect of serotonin reduces excitability of the anterior thalamus in wildtype mice and this may be impaired in DS mice. Continued work will investigate how anterior thalamus neurons integrate serotonergic, glutamatergic, and GABAergic input and whether serotonin modulation suppresses seizure activity in the anterior thalamus circuitry.

Funding: This work was supported by the Seale Innovation Fund and Commonwealth Health Research Board.