Anandamide Signaling Augmentation Rescues Amygdala Synaptic Function and Comorbid Emotional Alterations in a Model of Epilepsy.

Epilepsy is often associated with emotional disturbances and the endocannabinoid (eCB) system tunes synaptic transmission in brain regions regulating emotional behavior. Thus, persistent alteration of eCB signaling after repeated seizures may contribute to the development of epilepsy-related emotional disorders. Here we report that repeatedly eliciting seizures (kindling) in the amygdala caused a long-term increase in anxiety and impaired fear memory retention, which was paralleled by an imbalance in GABA/glutamate presynaptic activity and alteration of synaptic plasticity in the basolateral amygdala (BLA), in male rats. Anandamide (AEA) content was downregulated after repeated seizures, and pharmacological enhancement of AEA signaling rescued seizure-induced anxiety by restoring the tonic control of the eCB signaling over glutamatergic transmission. Moreover, AEA signaling augmentation also rescued the seizure-induced alterations of fear memory by restoring the phasic control of eCB signaling over GABAergic activity and plasticity in the BLA. These results indicate that modulation of AEA signaling represents a potential and promising target for the treatment of comorbid emotional dysfunction associated with epilepsy.SIGNIFICANCE STATEMENT Epilepsy is a heterogeneous neurologic disorder commonly associated with comorbid emotional alterations. However, the management of epilepsy is usually restricted to the control of seizures. The endocannabinoid (eCB) system, particularly anandamide (AEA) signaling, controls neuronal excitability and seizure expression and regulates emotional behavior. We found that repeated seizures cause an allostatic maladaptation of AEA signaling in the amygdala that drives emotional alterations. Boosting AEA signaling through inhibition of its degradative enzyme, fatty acid amide hydrolase (FAAH), restored both synaptic and behavioral alterations. FAAH inhibitors dampen seizure activity in animal models and are used in clinical studies to treat the negative consequences associated with stress. Thereby, they are accessible and can be clinically evaluated to treat both seizures and comorbid conditions associated with epilepsy.