Circuit‐Selective FAAH Inhibition Suppresses Experimental Absence Seizures

Background: Childhood absence epilepsy (CAE) arises from dysfunctional corticothalamic networks generating spike wave discharges (SWDs) and behavioral arrest. Despite available treatments, a significant proportion of patients remain pharmacoresistant and develop neuropsychiatric comorbidities. The endocannabinoid system (ECS), through activity-dependent signaling, is a key regulator of synaptic and network stability, but its therapeutic potential in absence epilepsy remains unresolved. Aims: To determine whether selective elevation of endogenous cannabinoid tone—particularly anandamide (AEA)—via inhibition of fatty acid amide hydrolase (FAAH) suppresses absence seizures and to define the contribution of thalamic mechanisms. Materials and Methods: Video-EEG recordings were performed in Genetic Absence Epilepsy Rats from Strasbourg (GAERS), combining automated detection and blinded validation of SWDs. The irreversible FAAH inhibitor PF-04457845 was administered acutely and subchronically and also delivered via bilateral microinfusion into the ventrobasal (VB) thalamus. Seizure number, total seizure time, and seizure duration were quantified. Results: FAAH inhibition produced a robust and sustained reduction in absence seizures, primarily by decreasing seizure number and cumulative seizure time, with minimal effects on seizure duration. These effects were observed following both acute and repeated systemic administrations, without evidence of tolerance. Importantly, focal VB microinfusion of PF-04457845 reproduced the anti-absence effects, demonstrating that thalamic enhancement of endocannabinoid signaling is sufficient to attenuate pathological network activity. These effects are consistent with increased brain AEA levels and enhanced activity-dependent CB1 receptor signaling. Discussion: Our findings indicate that selective amplification of endogenous cannabinoid signaling—likely driven by increased AEA availability—suppresses absence-like activity by modulating thalamocortical network dynamics. In contrast to direct CB1 receptor agonists, which exacerbate absence seizures, FAAH inhibition preserves the spatial and temporal specificity of ECS, enabling circuit-restricted modulation of excitability. The VB thalamus emerges as a critical locus for ECS-mediated control of seizure generation. Conclusion: FAAH inhibition represents a mechanistically distinct and circuit-selective strategy to suppress absence seizures, likely through elevation of endogenous AEA and targeted modulation of thalamocortical networks. These findings support further translational development of FAAH inhibitors as potential therapies for CAE.