Wiring and firing neuronal networks: endocannabinoids take center stage

Harkany, Tibor; Mackie, Ken; Doherty, Patrick

doi:10.1016/j.conb.2008.08.007

Cited by 102 publications

(79 citation statements)

References 50 publications

(38 reference statements)

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“…The amount of transmitter that is released, and the postsynaptic sensitivity to the transmitter are both malleable, with changes in one or the other resulting in a change in synaptic strength, with this process often being described as 'synaptic plasticity'. Perhaps not surprisingly, there are numerous ways to produce a change in synaptic strength, and a wide range of molecular mechanisms, including eCB signalling, have been identified that contribute to this [47]. In this context, eCB signalling has been recognized for some time to regulate some forms of activity-dependent synaptic plasticity.…”

Section: Diacylglycerol Lipase-dependent Endocannabinoid Signalling Imentioning

confidence: 99%

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The diacylglycerol lipases: structure, regulation and roles in and beyond endocannabinoid signalling

Reisenberg

Singh

Williams

et al. 2012

Phil. Trans. R. Soc. B

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121

119

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The diacylglycerol lipases (DAGLs) hydrolyse diacylglycerol to generate 2-arachidonoylglycerol (2-AG), the most abundant ligand for the CB 1 and CB 2 cannabinoid receptors in the body. DAGL-dependent endocannabinoid signalling regulates axonal growth and guidance during development, and is required for the generation and migration of new neurons in the adult brain. At developed synapses, 2-AG released from postsynaptic terminals acts back on presynaptic CB 1 receptors to inhibit the secretion of both excitatory and inhibitory neurotransmitters, with this DAGL-dependent synaptic plasticity operating throughout the nervous system. Importantly, the DAGLs have functions that do not involve cannabinoid receptors. For example, 2-AG is the precursor of arachidonic acid in a pathway that maintains the level of this essential lipid in the brain and other organs. This pathway also drives the cyclooxygenase-dependent generation of inflammatory prostaglandins in the brain, which has recently been implicated in the degeneration of dopaminergic neurons in Parkinson's disease. Remarkably, we still know very little about the mechanisms that regulate DAGL activity-however, key insights can be gleaned by homology modelling against other a/b hydrolases and from a detailed examination of published proteomic studies and other databases. These identify a regulatory loop with a highly conserved signature motif, as well as phosphorylation and palmitoylation as post-translational mechanisms likely to regulate function.

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Section: Diacylglycerol Lipase-dependent Endocannabinoid Signalling Imentioning

confidence: 99%

“…There are numerous eCB responses that the DAGLs might or might not drive, but we will limit our comments to three aspects of the 'wiring and firing' of the brain. These have recently been reviewed in considerable detail [29,47]; so we simply focus on the 'take home' messages.…”

Section: Diacylglycerol Lipase-dependent Endocannabinoid Signalling Imentioning

confidence: 99%

The diacylglycerol lipases: structure, regulation and roles in and beyond endocannabinoid signalling

Reisenberg

Singh

Williams

et al. 2012

Phil. Trans. R. Soc. B

Self Cite

121

119

View full text Add to dashboard Cite

show abstract

“…CB1 retrograde signaling appears to play a major role in synaptic plasticity and learning across the lifespan (Harkany et al, 2008). This suggests that connectivity among brain regions may be especially sensitive to either endogenous variations in CB1 function or distribution, or chronic CB use.…”

Section: Introductionmentioning

confidence: 99%

Structural Network Topology Revealed by White Matter Tractography in Cannabis Users: A Graph Theoretical Analysis

et al. 2011

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Endocannabinoid receptors modulate synaptic plasticity in the brain and may therefore impact cortical connectivity not only during development but also in response to substance abuse in later life. Such alterations may not be evident in volumetric measures utilized in brain imaging, but could affect the local and global organization of brain networks. To test this hypothesis, we used a novel computational approach to estimate network measures of structural brain connectivity derived from diffusion tensor imaging (DTI) and white matter tractography. Twelve adult cannabis (CB) users and 13 healthy subjects were evaluated using a graph theoretic analysis of both global and local brain network properties. Structural brain networks in both CB subjects and controls exhibited robust small-world network attributes in both groups. However, CB subjects showed significantly decreased global network efficiency and significantly increased clustering coefficients (degree to which nodes tend to cluster around individual nodes). CB subjects also exhibited altered patterns of local network organization in the cingulate region. Among all subjects, schizotypal and impulsive personality characteristics correlated with global efficiency but not with the clustering coefficient. Our data indicate that structural brain networks in CB subjects are less efficiently integrated and exhibit altered regional connectivity. These differences in network properties may reflect physiological processes secondary to substance abuse-induced synaptic plasticity, or differences in brain organization that increase vulnerability to substance use.

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“…In the case of 2-AG, the primary route of synthesis is likely to be via hydrolysis of diacylglycerol (DAG) by one or other of two highly related sn-1-specific DAG lipases (DAGL␣ and DAGL␤) (Bisogno et al, 2003). These enzymes make a releasable pool of 2-AG in response to stimuli that activate eCB signaling (Bisogno et al, 2003;Jung et al, 2007) and are expressed at the right time and place to serve as a source of 2-AG to drive CB 1 -dependent axonal growth and guidance, adult neurogenesis, and synthesis of a retrograde synaptic messenger at CB 1 -positive synapses throughout the brain (Harkany et al, 2008). Nonetheless, the extent to which the enzymes make 2-AG and their individual involvement in eCB signaling remains to be tested.…”

Section: Introductionmentioning

confidence: 99%

Loss of Retrograde Endocannabinoid Signaling and Reduced Adult Neurogenesis in Diacylglycerol Lipase Knock-out Mice

et al. 2010

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Endocannabinoids (eCBs) function as retrograde signaling molecules at synapses throughout the brain, regulate axonal growth and guidance during development, and drive adult neurogenesis. There remains a lack of genetic evidence as to the identity of the enzyme(s) responsible for the synthesis of eCBs in the brain. Diacylglycerol lipase-␣ (DAGL␣) and -␤ (DAGL␤) synthesize 2-arachidonoyl-glycerol (2-AG), the most abundant eCB in the brain. However, their respective contribution to this and to eCB signaling has not been tested. In the present study, we show ϳ80% reductions in 2-AG levels in the brain and spinal cord in DAGL␣ Ϫ/Ϫ mice and a 50% reduction in the brain in DAGL␤ Ϫ/Ϫ mice. In contrast, DAGL␤ plays a more important role than DAGL␣ in regulating 2-AG levels in the liver, with a 90% reduction seen in DAGL␤ Ϫ/Ϫ mice. Levels of arachidonic acid decrease in parallel with 2-AG, suggesting that DAGL activity controls the steady-state levels of both lipids. In the hippocampus, the postsynaptic release of an eCB results in the transient suppression of GABAmediated transmission at inhibitory synapses; we now show that this form of synaptic plasticity is completely lost in DAGL␣ Ϫ/Ϫ animals and relatively unaffected in DAGL␤ Ϫ/Ϫ animals. Finally, we show that the control of adult neurogenesis in the hippocampus and subventricular zone is compromised in the DAGL␣ Ϫ/Ϫ and/or DAGL␤ Ϫ/Ϫ mice. These findings provide the first evidence that DAGL␣ is the major biosynthetic enzyme for 2-AG in the nervous system and reveal an essential role for this enzyme in regulating retrograde synaptic plasticity and adult neurogenesis.

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Wiring and firing neuronal networks: endocannabinoids take center stage

Cited by 102 publications

References 50 publications

The diacylglycerol lipases: structure, regulation and roles in and beyond endocannabinoid signalling

The diacylglycerol lipases: structure, regulation and roles in and beyond endocannabinoid signalling

Structural Network Topology Revealed by White Matter Tractography in Cannabis Users: A Graph Theoretical Analysis

Loss of Retrograde Endocannabinoid Signaling and Reduced Adult Neurogenesis in Diacylglycerol Lipase Knock-out Mice

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