Thalamic 5-HT2A receptor activation reduces GABA uptake, increases tonic GABAA inhibition and induces absence seizures in Wistar rats

Renewed interest in psychedelic therapeutics has brought serotonin 5-HT2A receptors (5-HT2ARs) back into focus. Given the role of the thalamus in sensory integration and network synchronization, we examined the expression, developmental regulation, and functional impact of thalamic 5-HT2ARs, with particular emphasis on their interaction with extrasynaptic GABAA receptors and the generation of aberrant thalamocortical rhythms in Wistar rats. Immunofluorescence revealed a developmental increase of 5-HT2AR expression in both the reticular thalamic nucleus (NRT) and ventrobasal (VB) thalamus, that is accompanied by a shift in VB expression from GABAergic interneurons in juveniles to thalamocortical (TC) neurons in adults. Astrocyte density increased in both regions, more prominently in the NRT than in the VB, with approximately half of astrocytes expressing 5-HT2ARs regardless of age or region. Activation of 5-HT2ARs with the potent agonist TCB-2 reduced thalamic GABA uptake, an effect that was occluded in the presence of GAT1 inhibitor NO711. Patch-clamp recordings showed that TCB-2 enhanced tonic GABAA currents in VB TC neurons. This effect was absent in δ-subunit KO mice and was unaffected by blockade of postsynaptic G-protein signaling or phospholipase C pathways in TC neurons, suggesting that it is not dependent on postsynaptic signaling mechanisms. EEG recordings in freely moving rats showed that bilateral microinjection of TCB-2 into the VB induced spike-and-wave discharges accompanied by behavioral arrest that were blocked by ethosuximide, indicating that they were absence seizures. In summary, these findings support a mechanism, through which serotonergic signaling via 5-HT2ARs can shape thalamocortical network dynamics and increase susceptibility to aberrant rhythmic activity, which could potentially occur under conditions of altered serotonergic tone.