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

Epilepsy is often associated with emotional disturbances. The endocannabinoid (eCB) system tunes synaptic transmission in brain regions regulating emotional behaviour. Persistent alteration of eCB signalling after repeated seizures may contribute to the development of epilepsy-related emotional disorders. 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 signalling rescued seizure-induced anxiety by restoring the tonic control of the eCB signalling over glutamatergic transmission. Moreover, AEA signalling augmentation also rescued the seizure-induced alterations of fear memory by restoring the phasic control of eCB signalling over GABAergic activity and plasticity in the BLA. These results indicate that modulation of AEA signalling represents a potential promising target for the treatment of comorbid emotional dysfunction associated with epilepsy. Significance Statement Epilepsy is a heterogeneous neurological disorder commonly associated with comorbid emotional alterations. However, the management of epilepsy is usually restricted to the control of seizures. The endocannabinoid system, particularly anandamide signalling, controls neuronal excitability and seizure expression and regulates emotional behaviour. We found that repeated seizures cause an allostatic maladaptation of anandamide signalling in the amygdala that drives emotional alterations. Boosting anandamide signalling through inhibition of its degradative enzyme, fatty acid amide hydrolase (FAAH), restored both synaptic and behavioural 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 to be clinically evaluated to treat both seizures and comorbid conditions associated with epilepsy.