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.
Highlights
Alterations in synaptic plasticity have been associated with the occurrence of emotional disorders and impairment in memory processes [1, 2]
We investigated whether impaired AEA signaling in fatty acid amide hydrolase (FAAH)-overexpressing mice leads to alterations of endocannabinoid-regulated synaptic plasticity (LTP, long-term depression (LTD), depolarization-induced suppression of excitation (DSE), DSI), emotional responses and memory processes
Co-transfection of Stop-FAAH and Cre-expressing plasmids in HEK293 cells resulted in excision of the transcriptional Stop cassette and initiation of transcription of HA-FAAH
Summary
Alterations in synaptic plasticity have been associated with the occurrence of emotional disorders (anxiety, depression) and impairment in memory processes [1, 2]. Alterations in endocannabinoid system activity are implicated in dysregulated emotional and cognitive responses [3]. Given this observation, endocannabinoid signaling via anandamide (AEA) has been proposed to be a promising therapeutic target for a variety of emotion-related disorders [4]. AEA synthesis in neurons was reported to occur both in presynaptic and postsynaptic sites [7]. The main AEA degrading enzyme is fatty acid amide hydrolase (FAAH), an integral membrane serine hydrolase highly expressed in the brain and located in somata and dendrites of neurons, postsynaptically opposed to axon fibers expressing CB1 receptor [8, 9].
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