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.

中文翻译：

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海马谷氨酸能神经元中的anandamide / palmitoylethanolamide信号传导受损，会改变突触可塑性，学习和情绪反应。

经由anandamide（AEA）的内源性大麻素信号传导涉及多种神经元功能，并被认为是许多与情感有关的疾病的有希望的治疗靶标。主要的AEA降解酶是脂肪酸酰胺水解酶（FAAH）。FAAH的遗传删除和药理抑制作用可减轻啮齿动物和人类的焦虑，并改善其情绪反应和记忆力。作为补充，减少AEA信号传导的机制和影响还有待详细描述。在本研究中，使用Cre / loxP系统与腺相关病毒（AAV）介导的递送系统相结合，FAAH在成年小鼠海马CA1-CA3谷氨酸能神经元中选择性过表达。这种方法导致CA1-CA3神经元的突触后位点发生特定的FAAH过表达，导致FAAH的酶促活性增加，并且，因此，降低了海马的AEA和棕榈酰乙醇酰胺（PEA）的水平，但是第二主要内源性大麻素2-花生四烯酰基甘油（2-AG）和油酰基乙醇酰胺（OEA）的水平没有变化。电生理学记录显示兴奋性和抑制性突触活性以及长期增强（LTP）均得到增强。相反，兴奋性和抑制性长期抑制（LTD）和短期突触可塑性，表现为去极化诱导的兴奋抑制（DSE）和抑制（DSI），保持不变。海马突触活动的这些变化与焦虑样行为的增加，物体识别记忆的缺乏和厌恶记忆的消失有关。这项研究表明，AEA不参与海马的短期可塑性，