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.
Gao
Ying
Y
Neuroscience Discovery, Pfizer Research, Princeton, New Jersey 08543, and Wolfson Centre for Age-Related Diseases, King's College London, London SE1 1UL, United Kingdom.
Vasilyev
Dmitry V
DV
Goncalves
Maria Beatriz
MB
Howell
Fiona V
FV
Hobbs
Carl
C
Reisenberg
Melina
M
Shen
Ru
R
Zhang
Mei-Yi
MY
Strassle
Brian W
BW
Lu
Peimin
P
Mark
Lilly
L
Piesla
Michael J
MJ
Deng
Kangwen
K
Kouranova
Evguenia V
EV
Ring
Robert H
RH
Whiteside
Garth T
GT
Bates
Brian
B
Walsh
Frank S
FS
Williams
Gareth
G
Pangalos
Menelas N
MN
Samad
Tarek A
TA
Doherty
Patrick
P
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