A diacylglycerol lipase-CB2 cannabinoid pathway regulates adult subventricular zone neurogenesis in an age-dependent manner.
The subventricular zone (SVZ) is a major site of neurogenesis in the adult. We now show that ependymal and proliferating cells in the adult mouse SVZ express diacylglycerol lipases (DAGLs), enzymes that synthesise a CB1/CB2 cannabinoid receptor ligand. DAGL and CB2 antagonists inhibit the proliferation of cultured neural stem cells, and the proliferation of progenitor cells in young animals. Furthermore, CB2 agonists stimulate progenitor cell proliferation in vivo, with this effect being more pronounced in older animals. A similar response was seen with a fatty acid amide hydrolase (FAAH) inhibitor that limits degradation of endocannabinoids. The effects on proliferation were mirrored in changes in the number of neuroblasts migrating from the SVZ to the olfactory bulb (OB). In this context, CB2 antagonists reduced the number of newborn neurons appearing in the OB in the young adult animals while CB2 agonists stimulated this in older animals. These data identify CB2 receptor agonists and FAAH inhibitors as agents that can counteract the naturally observed decline in adult neurogenesis that is associated with ageing.
Wolfson Centre for Age-Related Diseases, King's College, London SE1 9RT, UK.
Maria Beatriz
MB
Goncalves
Philipp
P
Suetterlin
Ping
P
Yip
Francisco
F
Molina-Holgado
Deborah J
DJ
Walker
Madeleine J
MJ
Oudin
Marc P
MP
Zentar
Steven
S
Pollard
Rafael J
RJ
Yáñez-Muñoz
Gareth
G
Williams
Frank S
FS
Walsh
Menelas N
MN
Pangalos
Patrick
P
Doherty
D000367:Age Factors; D000375:Aging / Q000502:physiology*; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured; D002552:Cerebral Ventricles / Q000166:cytology / Q000201:enzymology / Q000254:growth & development*; D005260:Female; D008071:Lipoprotein Lipase / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000201:enzymology / Q000502:physiology; D043885:Receptor, Cannabinoid, CB2 / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology / Q000201:enzymology / Q000502:physiology
D043885:Receptor, Cannabinoid, CB2; D008071:Lipoprotein Lipase