The endocannabinoid 2-arachidonoylglycerol (2-AG) regulates neurotransmission and neuroinflammation by activating CB 1 cannabinoid receptors on neurons and CB 2 cannabinoid Correspondence should be addressed to N.S. (nstella@uw.edu). 11 These authors contributed equally to this work.Note: Supplementary information is available on the Nature Neuroscience website. Competing Financial Interests:The authors declare no competing financial interests.Reprints and permissions information is available online at http://www.nature.com/reprintsandpermissions/. NIH Public Access Author ManuscriptNat Neurosci. Author manuscript; available in PMC 2011 February 1. Published in final edited form as:Nat Neurosci. 2010 August ; 13(8): 951-957. doi:10.1038/nn.2601. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript receptors on microglia. Enzymes that hydrolyze 2-AG, such as monoacylglycerol lipase, regulate the accumulation and efficacy of 2-AG at cannabinoid receptors. We found that the recently described serine hydrolase α-β-hydrolase domain 6 (ABHD6) also controls the accumulation and efficacy of 2-AG at cannabinoid receptors. In cells from the BV-2 microglia cell line, ABHD6 knockdown reduced hydrolysis of 2-AG and increased the efficacy with which 2-AG can stimulate CB 2 -mediated cell migration. ABHD6 was expressed by neurons in primary culture and its inhibition led to activitydependent accumulation of 2-AG. In adult mouse cortex, ABHD6 was located postsynaptically and its selective inhibition allowed the induction of CB 1 -dependent long-term depression by otherwise subthreshold stimulation. Our results indicate that ABHD6 is a rate-limiting step of 2-AG signaling and is therefore a bona fide member of the endocannabinoid signaling system.In the nervous system, the endocannabinoids (eCBs) arachidonoylethanolamide (anandamide) and 2-AG are produced and inactivated by neurons and glia 1,2 . The production of eCBs increases in response to specific stimuli, including membrane receptor activation, ion channel opening and calcium influx 2 . eCBs are inactivated by cellular uptake followed by intracellular enzymatic hydrolysis 3,4 . The balance between this production and inactivation dictates the levels of extracellular eCB accumulation and the ensuing activation of CB 1 receptors expressed by neurons (regulating neurotransmitter release) and CB 2 receptors expressed by microglia (regulating their motility and ability to produce immunomodulators) [4][5][6][7] . Thus, the enzymatic steps that control the production and inactivation of eCBs constitute promising molecular targets for indirectly modulating CB 1 and CB 2 receptor activity, and thereby controlling neurotransmission and neuroinflammation.Of all the steps that control the accumulation of eCBs, the hydrolytic enzymes that inactivate anandamide and 2-AG represent the most promising pharmacological and genetic targets for fine-tuning the local accumulation of these lipid transmitters. Inhibition of fatty acid amide hydrolase (FAAH) increases...

Chronic exposure to drugs of abuse induces countless modifications in brain physiology. However, the neurobiological adaptations specifically associated with the transition to addiction are unknown. Cocaine self-administration rapidly suppresses long-term depression (LTD), an important form of synaptic plasticity in the nucleus accumbens. Using a rat model of addiction, we found that animals that progressively develop the behavioral hallmarks of addiction have permanently impaired LTD, whereas LTD is progressively recovered in nonaddicted rats maintaining a controlled drug intake. By making drug seeking consistently resistant to modulation by environmental contingencies and consequently more and more inflexible, a persistently impaired LTD could mediate the transition to addiction.

The corollaries of the obesity epidemic that plagues developed societies are malnutrition and resulting biochemical imbalances. Low levels of essential n-3 polyunsaturated fatty acids (n-3 PUFAs) have been linked to neuropsychiatric diseases, but the underlying synaptic alterations are mostly unknown. We found that lifelong n-3 PUFAs dietary insufficiency specifically ablates long-term synaptic depression mediated by endocannabinoids in the prelimbic prefrontal cortex and accumbens. In n-3-deficient mice, presynaptic cannabinoid CB(1) receptors (CB(1)Rs) normally responding to endocannabinoids were uncoupled from their effector G(i/o) proteins. Finally, the dietary-induced reduction of CB(1)R functions in mood-controlling structures was associated with impaired emotional behavior. These findings identify a plausible synaptic substrate for the behavioral alterations caused by the n-3 PUFAs deficiency that is often observed in western diets.

BackgroundCannabinoids have deleterious effects on prefrontal cortex (PFC)-mediated functions and multiple evidences link the endogenous cannabinoid (endocannabinoid) system, cannabis use and schizophrenia, a disease in which PFC functions are altered. Nonetheless, the molecular composition and the physiological functions of the endocannabinoid system in the PFC are unknown.Methodology/Principal FindingsHere, using electron microscopy we found that key proteins involved in endocannabinoid signaling are expressed in layers V/VI of the mouse prelimbic area of the PFC: presynaptic cannabinoid CB1 receptors (CB1R) faced postsynaptic mGluR5 while diacylglycerol lipase α (DGL-α), the enzyme generating the endocannabinoid 2-arachidonoyl-glycerol (2-AG) was expressed in the same dendritic processes as mGluR5. Activation of presynaptic CB1R strongly inhibited evoked excitatory post-synaptic currents. Prolonged synaptic stimulation at 10Hz induced a profound long-term depression (LTD) of layers V/VI excitatory inputs. The endocannabinoid -LTD was presynaptically expressed and depended on the activation of postsynaptic mGluR5, phospholipase C and a rise in postsynaptic Ca2+ as predicted from the localization of the different components of the endocannabinoid system. Blocking the degradation of 2-AG (with URB 602) but not of anandamide (with URB 597) converted subthreshold tetanus to LTD-inducing ones. Moreover, inhibiting the synthesis of 2-AG with Tetrahydrolipstatin, blocked endocannabinoid-mediated LTD. All together, our data show that 2-AG mediates LTD at these synapses.Conclusions/SignificanceOur data show that the endocannabinoid -retrograde signaling plays a prominent role in long-term synaptic plasticity at the excitatory synapses of the PFC. Alterations of endocannabinoid -mediated synaptic plasticity may participate to the etiology of PFC-related pathologies.

Summary The biophysical features of neurons shape information processing in the brain. Cortical neurons are larger in humans than in other species, but it is unclear how their size affects synaptic integration. Here, we perform direct electrical recordings from human dendrites and report enhanced electrical compartmentalization in layer 5 pyramidal neurons. Compared to rat dendrites, distal human dendrites provide limited excitation to the soma, even in the presence of dendritic spikes. Human somas also exhibit less bursting due to reduced recruitment of dendritic electrogenesis. Finally, we find that decreased ion channel densities result in higher input resistance and underlie the lower coupling of human dendrites. We conclude that the increased length of human neurons alters their input-output properties, which will impact cortical computation.

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Defining the drug-induced neuroadaptations specifically associated with the behavioral manifestation of addiction is a daunting task. To address this issue, we used a behavioral model that differentiates rats controlling their drug use (Non-Addict-like) from rats undergoing transition to addiction (Addict-like). Dysfunctions in prefrontal cortex (PFC) synaptic circuits are thought to be responsible for the loss of control over drug taking that characterizes addicted individuals. Here, we studied the synaptic alterations in prelimbic PFC (pPFC) circuits associated with transition to addiction. We discovered that some of the changes induced by cocaine self-administration (SA), such as the impairment of the endocannabinoid-mediated long-term synaptic depression (eCB-LTD) was similarly abolished in Non-Addict- and Addict-like rats and thus unrelated to transition to addiction. In contrast, metabotropic glutamate receptor 2/3-mediated LTD (mGluR2/3-LTD) was specifically suppressed in Addict-like rats, which also show a concomitant postsynaptic plasticity expressed as a change in the relative contribution of AMPAR and NMDAR to basal glutamate-mediated synaptic transmission. Addiction-associated synaptic alterations in the pPFC were not fully developed at early stages of cocaine SA, when addiction-like behaviors are still absent, suggesting that pathological behaviors appear once the pPFC is compromised. These data identify specific synaptic impairments in the pPFC associated with addiction and support the idea that alterations of synaptic plasticity are core markers of drug dependence.

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