Loss of retrograde endocannabinoid signaling and reduced adult neurogenesis in diacylglycerol lipase knock-out mice.
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 (DAGLalpha) and -beta (DAGLbeta) 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 approximately 80% reductions in 2-AG levels in the brain and spinal cord in DAGLalpha(-/-) mice and a 50% reduction in the brain in DAGLbeta(-/-) mice. In contrast, DAGLbeta plays a more important role than DAGLalpha in regulating 2-AG levels in the liver, with a 90% reduction seen in DAGLbeta(-/-) 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 DAGLalpha(-/-) animals and relatively unaffected in DAGLbeta(-/-) animals. Finally, we show that the control of adult neurogenesis in the hippocampus and subventricular zone is compromised in the DAGLalpha(-/-) and/or DAGLbeta(-/-) mice. These findings provide the first evidence that DAGLalpha 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.
Neuroscience Discovery, Pfizer Research, Princeton, New Jersey 08543, and Wolfson Centre for Age-Related Diseases, King's College London, London SE1 1UL, United Kingdom.
Ying
Y
Gao
Dmitry V
DV
Vasilyev
Maria Beatriz
MB
Goncalves
Fiona V
FV
Howell
Carl
C
Hobbs
Melina
M
Reisenberg
Ru
R
Shen
Mei-Yi
MY
Zhang
Brian W
BW
Strassle
Peimin
P
Lu
Lilly
L
Mark
Michael J
MJ
Piesla
Kangwen
K
Deng
Evguenia V
EV
Kouranova
Robert H
RH
Ring
Garth T
GT
Whiteside
Brian
B
Bates
Frank S
FS
Walsh
Gareth
G
Williams
Menelas N
MN
Pangalos
Tarek A
TA
Samad
Patrick
P
Doherty
D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D063385:Cannabinoid Receptor Modulators / Q000502:physiology*; D063388:Endocannabinoids; D005989:Glycerides / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D008071:Lipoprotein Lipase / Q000235:genetics*; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D055495:Neurogenesis; D009473:Neuronal Plasticity; D015398:Signal Transduction; D013116:Spinal Cord / Q000378:metabolism; D013569:Synapses / Q000502:physiology
D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D005989:Glycerides; C094503:glyceryl 2-arachidonate; D008071:Lipoprotein Lipase