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

Ying Gao; Dmitry V. Vasilyev; Maria Beatriz Goncalves; Fiona V. Howell; Carl Hobbs; Melina Reisenberg; Ru Shen; Mei-Yi Zhang; Brian W. Strassle; Peimin Lu; Lilly Mark; Michael J. Piesla; Kangwen Deng; Evguenia V. Kouranova; Robert H. Ring; Garth T. Whiteside; Brian Bates; Frank S. Walsh; Gareth Williams; Menelas N. Pangalos; Tarek A. Samad; Patrick Doherty

doi:10.1523/JNEUROSCI.5693-09.2010

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

Ying Gao, Dmitry V. Vasilyev, Maria Beatriz Goncalves, Fiona V. Howell, Carl Hobbs, Melina Reisenberg, Ru Shen, Mei-Yi Zhang, Brian W. Strassle, Peimin Lu, Lilly Mark, Michael J. Piesla, Kangwen Deng, Evguenia V. Kouranova, Robert H. Ring, Garth T. Whiteside, Brian Bates, Frank S. Walsh, Gareth Williams, Menelas N. PangalosTarek A. Samad, Patrick Doherty

Wolfson SPaRC

Research output: Contribution to journal › Article › peer-review

386 Citations (Scopus)

Abstract

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-alpha (DAGL alpha) and -beta (DAGL alpha) 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 similar to 80% reductions in 2-AG levels in the brain and spinal cord in DAGL alpha(-/-) mice and a 50% reduction in the brain in DAGL beta(-/-) mice. In contrast, DAGL beta plays a more important role than DAGL alpha in regulating 2-AG levels in the liver, with a 90% reduction seen in DAGL beta(-/-) 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 GABA-mediated transmission at inhibitory synapses; we now show that this form of synaptic plasticity is completely lost in DAGL alpha(-/-) animals and relatively unaffected in DAGL beta(-/-) animals. Finally, we show that the control of adult neurogenesis in the hippocampus and subventricular zone is compromised in the DAGL alpha(-/-) and/or DAGL beta(-/-) mice. These findings provide the first evidence that DAGL alpha 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.

Original language	English
Pages (from-to)	2017 - 2024
Number of pages	8
Journal	Journal of Neuroscience
Volume	30
Issue number	6
DOIs	https://doi.org/10.1523/JNEUROSCI.5693-09.2010
Publication status	Published - 10 Feb 2010

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Gao, Y., Vasilyev, D. V., Goncalves, M. B., Howell, F. V., Hobbs, C., Reisenberg, M., Shen, R., Zhang, M.-Y., Strassle, B. W., Lu, P., Mark, L., Piesla, M. J., Deng, K., Kouranova, E. V., Ring, R. H., Whiteside, G. T., Bates, B., Walsh, F. S., Williams, G., ... Doherty, P. (2010). Loss of Retrograde Endocannabinoid Signaling and Reduced Adult Neurogenesis in Diacylglycerol Lipase Knock-out Mice. Journal of Neuroscience, 30(6), 2017 - 2024. https://doi.org/10.1523/JNEUROSCI.5693-09.2010

@article{381027c496bb470faf9b9612fa3b0ba3,

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

abstract = "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-alpha (DAGL alpha) and -beta (DAGL alpha) 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 similar to 80% reductions in 2-AG levels in the brain and spinal cord in DAGL alpha(-/-) mice and a 50% reduction in the brain in DAGL beta(-/-) mice. In contrast, DAGL beta plays a more important role than DAGL alpha in regulating 2-AG levels in the liver, with a 90% reduction seen in DAGL beta(-/-) 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 GABA-mediated transmission at inhibitory synapses; we now show that this form of synaptic plasticity is completely lost in DAGL alpha(-/-) animals and relatively unaffected in DAGL beta(-/-) animals. Finally, we show that the control of adult neurogenesis in the hippocampus and subventricular zone is compromised in the DAGL alpha(-/-) and/or DAGL beta(-/-) mice. These findings provide the first evidence that DAGL alpha 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.",

author = "Ying Gao and Vasilyev, {Dmitry V.} and Goncalves, {Maria Beatriz} and Howell, {Fiona V.} and Carl Hobbs and Melina Reisenberg and Ru Shen and Mei-Yi Zhang and Strassle, {Brian W.} and Peimin Lu and Lilly Mark and Piesla, {Michael J.} and Kangwen Deng and Kouranova, {Evguenia V.} and Ring, {Robert H.} and Whiteside, {Garth T.} and Brian Bates and Walsh, {Frank S.} and Gareth Williams and Pangalos, {Menelas N.} and Samad, {Tarek A.} and Patrick Doherty",

year = "2010",

month = feb,

day = "10",

doi = "10.1523/JNEUROSCI.5693-09.2010",

language = "English",

volume = "30",

pages = "2017 -- 2024",

journal = "Journal of Neuroscience",

issn = "1529-2401",

publisher = "Society for Neuroscience",

number = "6",

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Gao, Y, Vasilyev, DV, Goncalves, MB, Howell, FV, Hobbs, C, Reisenberg, M, Shen, R, Zhang, M-Y, Strassle, BW, Lu, P, Mark, L, Piesla, MJ, Deng, K, Kouranova, EV, Ring, RH, Whiteside, GT, Bates, B, Walsh, FS , Williams, G, Pangalos, MN, Samad, TA & Doherty, P 2010, 'Loss of Retrograde Endocannabinoid Signaling and Reduced Adult Neurogenesis in Diacylglycerol Lipase Knock-out Mice', Journal of Neuroscience, vol. 30, no. 6, pp. 2017 - 2024. https://doi.org/10.1523/JNEUROSCI.5693-09.2010

TY - JOUR

T1 - Loss of Retrograde Endocannabinoid Signaling and Reduced Adult Neurogenesis in Diacylglycerol Lipase Knock-out Mice

AU - Gao, Ying

AU - Vasilyev, Dmitry V.

AU - Goncalves, Maria Beatriz

AU - Howell, Fiona V.

AU - Hobbs, Carl

AU - Reisenberg, Melina

AU - Shen, Ru

AU - Zhang, Mei-Yi

AU - Strassle, Brian W.

AU - Lu, Peimin

AU - Mark, Lilly

AU - Piesla, Michael J.

AU - Deng, Kangwen

AU - Kouranova, Evguenia V.

AU - Ring, Robert H.

AU - Whiteside, Garth T.

AU - Bates, Brian

AU - Walsh, Frank S.

AU - Williams, Gareth

AU - Pangalos, Menelas N.

AU - Samad, Tarek A.

AU - Doherty, Patrick

PY - 2010/2/10

Y1 - 2010/2/10

N2 - 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-alpha (DAGL alpha) and -beta (DAGL alpha) 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 similar to 80% reductions in 2-AG levels in the brain and spinal cord in DAGL alpha(-/-) mice and a 50% reduction in the brain in DAGL beta(-/-) mice. In contrast, DAGL beta plays a more important role than DAGL alpha in regulating 2-AG levels in the liver, with a 90% reduction seen in DAGL beta(-/-) 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 GABA-mediated transmission at inhibitory synapses; we now show that this form of synaptic plasticity is completely lost in DAGL alpha(-/-) animals and relatively unaffected in DAGL beta(-/-) animals. Finally, we show that the control of adult neurogenesis in the hippocampus and subventricular zone is compromised in the DAGL alpha(-/-) and/or DAGL beta(-/-) mice. These findings provide the first evidence that DAGL alpha 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.

AB - 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-alpha (DAGL alpha) and -beta (DAGL alpha) 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 similar to 80% reductions in 2-AG levels in the brain and spinal cord in DAGL alpha(-/-) mice and a 50% reduction in the brain in DAGL beta(-/-) mice. In contrast, DAGL beta plays a more important role than DAGL alpha in regulating 2-AG levels in the liver, with a 90% reduction seen in DAGL beta(-/-) 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 GABA-mediated transmission at inhibitory synapses; we now show that this form of synaptic plasticity is completely lost in DAGL alpha(-/-) animals and relatively unaffected in DAGL beta(-/-) animals. Finally, we show that the control of adult neurogenesis in the hippocampus and subventricular zone is compromised in the DAGL alpha(-/-) and/or DAGL beta(-/-) mice. These findings provide the first evidence that DAGL alpha 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.

U2 - 10.1523/JNEUROSCI.5693-09.2010

DO - 10.1523/JNEUROSCI.5693-09.2010

M3 - Article

SN - 1529-2401

VL - 30

SP - 2017

EP - 2024

JO - Journal of Neuroscience

JF - Journal of Neuroscience

IS - 6

ER -

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

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