Impaired anandamide/palmitoylethanolamide signaling in hippocampal glutamatergic neurons alters synaptic plasticity, learning, and emotional responses

Abstract

Endocannabinoid signaling via anandamide (AEA) is implicated in a variety of neuronal functions and considered a promising therapeutic target for numerous emotion-related disorders. The major AEA degrading enzyme is fatty acid amide hydrolase (FAAH). Genetic deletion and pharmacological inhibition of FAAH reduce anxiety and improve emotional responses and memory in rodents and humans. Complementarily, the mechanisms and impact of decreased AEA signaling remain to be delineated in detail. In the present study, using the Cre/loxP system combined with an adeno-associated virus (AAV)-mediated delivery system, FAAH was selectively overexpressed in hippocampal CA1-CA3 glutamatergic neurons of adult mice. This approach led to specific FAAH overexpression at the postsynaptic site of CA1-CA3 neurons, to increased FAAH enzymatic activity, and, in consequence, to decreased hippocampal levels of AEA and palmitoylethanolamide (PEA), but the levels of the second major endocannabinoid 2-arachidonoyl glycerol (2-AG) and of oleoylethanolamide (OEA) were unchanged. Electrophysiological recordings revealed an enhancement of both excitatory and inhibitory synaptic activity and of long-term potentiation (LTP). In contrast, excitatory and inhibitory long-term depression (LTD) and short-term synaptic plasticity, apparent as depolarization-induced suppression of excitation (DSE) and inhibition (DSI), remained unaltered. These changes in hippocampal synaptic activity were associated with an increase in anxiety-like behavior, and a deficit in object recognition memory and in extinction of aversive memory. This study indicates that AEA is not involved in hippocampal short-term plasticity, or eLTD and iLTD, but modulates glutamatergic transmission most likely via presynaptic sites, and that disturbances in this process impair learning and emotional responses.

Endocannabinoid System Components as Potential Biomarkers in Psychiatry

“…Interestingly, these effects were abolished by CB1r blockade, suggesting the implication of CB1r on URB597 effects (335,335). Similar results were obtained with the administration of URB597 into CA1 (Hipp) and BLA brain regions, showing a facilitation of extinction processes and attenuation of startle response, anxiety-and depression-like behaviors mediated by CB1r activation (133,336,337). Furthermore, URB597 administration additionally prevented the increase of CB1r levels in CA1 and BLA after rodent exposure to shock and reminder model of PTSD (321).…”

“…Since the direct pharmacological modulation of CB1r has provided some disappointing results, in recent years much attention has been paid to the therapeutic role of functional manipulation of the endogenous cannabinoid ligands AEA and 2-AG by inhibiting enzymatic degradation (FAAH and MAGL, respectively) or blocking reuptake (128)(129)(130)(131)(132). AEA plays a crucial role in emotional control (133). Inhibition of its degradation by FAAH or its reuptake induces a robust anxiolytic effect (134)(135)(136)(137)(138)(139)(140)(141)(142).…”

“…The involvement of CB1r in PTSD is supported by the presence of this receptor in brain areas regulating the response to stress and to changes observed in different animal models of PTSD. For instance, using a shock and reminder model of PTSD, higher mRNA levels of CB1r were detected in the BLA (133), and increased CB1r protein expression was found in the BLA and the CA1 region of the Hipp (321) of exposed mice as well. On the other hand, in a predator exposure-based PTSD model, anxietylike behavior was negatively correlated with CB1r gene expression in the PFC and the amygdaloid complex, whereas no changes were observed in the Hipp (322).…”

A Guide to Targeting the Endocannabinoid System in Drug Design

“…There is evidence on impact of FAAH activity on anxiety. FAAH overexpression in hippocampal CA1-CA3 glutamatergic neurons in a rodent model led to decreased AEA level in hippocampus, and resulted in anxiety-like behavior [112]. Certain FAAH genotypes result in increased activity of this enzyme, and in turn in reduced AEA levels [113,114].…”

Dynamic Balance of Microglia and Astrocytes Involved in the Remyelinating Effect of Ginkgolide B

“…Anxiety-and depression-like behavior and cognitive impairment have been observed in demyelinating lesions (Acharjee et al, 2013;Xu et al, 2019;Zimmermann et al, 2019). In this study, FS, EPM and TM tests were used to evaluate anxiety-and depression-like behavior and cognitive impairment.…”