A diacylglycerol lipase-CB2 cannabinoid pathway regulates adult subventricular zone neurogenesis in an age-dependent manner
Introduction
Determining where ligands for cannabinoid receptors are made is important for understanding the function of the endocannabinoid signalling system. 2-arachidonylglycerol (2-AG) is a ligand for the CB1/CB2 cannabinoid receptors (Stella et al., 1997, Sugiura et al., 1999) and two closely related diacylglycerol lipases (DAGLα and DAGLβ) that synthesise 2-AG have now been cloned (Bisogno et al., 2003). During development DAGL and CB1 transcripts can be found in newly born neurons (Begbie et al., 2004, Watson et al., 2008) with their protein products expressed in growing axons (Bisogno et al., 2003). Here DAGL and CB1 receptor function are required for the normal development of fasciculated axonal tracts (Brittis et al., 1996, Watson et al., 2008), a phenotype that is consistent with adhesion molecules promoting axonal growth by activating an FGF receptor/DAGL/CB1 signalling cascade in neuronal growth cones (Archer et al., 1999, Walsh and Doherty, 1996, Williams et al., 1994, Williams et al., 2003).
In the adult brain there is a requirement for the post-synaptic synthesis of an endocannabinoid that can function as a retrograde synaptic messenger (Wilson and Nicoll, 2002). Here, DAGLα and DAGLβ expression in neurons is restricted to dendrites, suggesting that they contribute to this endocannabinoid function (Bisogno et al., 2003). In support, DAGLα is enriched in dendritic spines at CB1-positive synapses throughout the adult nervous system (Lafourcade et al., 2007, Uchigashima et al., 2007, Yoshida et al., 2006). Thus, a switch in the expression for of the DAGLs from growing axons to dendrites allows for two fundamentally different endocannabinoid functions.
We now report the expression of DAGLs by ependymal and proliferating cells in the adult subventricular zone (SVZ). Here, neural stem cells generate rapidly dividing progenitors that migrate along the rostral migratory stream (RMS) and populate the olfactory bulb (OB) with new neurons (Altman, 1969, Kornack and Rakic, 2001, Lois and Alvarez-Buylla, 1994). SVZ neurogenesis is of additional interest in that it is modulated in neurodegenerative disease states and can act as a source of new neurons that can migrate to sites of injury (Alvarez-Buylla et al., 2000, Arvidsson et al., 2002, Curtis et al., 2007).
CB1 and CB2 receptors can modulate neural stem cell proliferation in culture (Molina-Holgado et al., 2007, Rueda et al., 2002) and/or in adult mice (Aguado et al., 2005, Jiang et al., 2005, Jin et al., 2004, Palazuelos et al., 2006). However, the role of DAGL activity and CB2 function has not been investigated in the SVZ. We now show that in the young adult, DAGL and CB2 antagonists inhibit cell proliferation in the SVZ, and that this is associated with a reduction in the appearance of new neurons in the OB. Furthermore, CB2 agonists stimulate cell proliferation in the SVZ of older animals and the appearance of new neurons in the OB. A similar effect on cell proliferation can be induced by inhibiting the activity of fatty acid amide hydrolase (FAAH), an enzyme involved in the breakdown of endocannabinoids (McKinney and Cravatt, 2005). This effect is also inhibited by a CB2 receptor antagonist. In contrast to the key role for the CB2 receptor, we find no evidence to support a role for the CB1 receptor in adult SVZ neurogenesis. Overall these data suggest that a rundown in endocannabinoid tone might be responsible for the reduced SVZ neurogenesis that is seen in older animals, and provide proof-of-concept evidence for CB2 receptors and FAAH as potential therapeutic targets to counteract this age-related phenomenon.
Section snippets
DAGL expression in the lateral wall of the ventricle in the SVZ and cultured neural stem cells
Recent evidence suggests that endocannabinoid signalling plays a role in neurogenesis in the adult SVZ (see Introduction), however little is known concerning the ability of the various cell types within the region to make ligands for cannabinoid receptors. In order to determine where 2-AG might be made in the lateral ventricle we labelled coronal sections of adult mouse brain with affinity purified antibodies to DAGLα. We found that DAGLα is highly expressed in essentially all of the ependymal
Discussion
The cloning of the vertebrate DAGLs (Bisogno et al., 2003) has allowed for an evaluation of where 2-AG might be synthesised “on-demand” in the developing and adult nervous system. During development the enzymes co-localise with the CB1 receptor on growing axons and play a key role in axonal growth and guidance (Watson et al., 2008). In the adult the enzymes are lost from axonal tracts, but found enriched in dendritic spines throughout the CNS (Bisogno et al., 2003). Restriction of the enzymes
Animals
Adult female C57BL/6 mice (Harlan UK Ltd., 6-week, 6-month and 20-month-old) and transient receptor potential vanilloid 1 (TRPV1) knockout mice were used in these studies. TRPV1 mice were as described previously (Caterina et al., 2000) and were purchased from The Jackson Laboratory (strain B6.129S4-Trpv1tm1Jul). All procedures were performed in accordance with U.K. Home Office regulations (Animals Scientific Procedures Act, 1986).
Surgery for intracerebroventricular (I.C.V.) cannulation
Mice were anaesthetized with an isoflurane/oxygen mixture and
Acknowledgments
Supported by grants form BBSRC, UK and Wyeth Research. We also thank Carl Hobbs and Fiona Howell for their excellent support.
References (50)
- et al.
The subventricular zone: source of neuronal precursors for brain repair
Prog. Brain Res.
(2000) - et al.
A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol
Chem. Biol.
(2007) - et al.
Fibroblast growth factor receptor function is required for the orderly projection of ganglion cell axons in the developing mammalian retina
Mol. Cell. Neurosci.
(1996) - et al.
Cannabinoid CB2 receptors: immunohistochemical localization in rat brain
Brain Res.
(2006) - et al.
The utility of Ki-67 and BrdU as proliferative markers of adult neurogenesis
J. Neurosci. Methods
(2002) - et al.
Intracerebroventricular infusion of insulin-like growth factor-I ameliorates the age-related decline in hippocampal neurogenesis
Neuroscience
(2001) - et al.
Functional neuroanatomy of the endocannabinoid system
Pharmacol. Biochem. Behav.
(2005) - et al.
The endocannabinoid anandamide inhibits neuronal progenitor cell differentiation through attenuation of the Rap1/B-Raf/ERK pathway
J. Biol. Chem.
(2002) - et al.
The fibroblast growth factor receptor Acid box is essential for interactions with N-cadherin and all of the major isoforms of neural cell adhesion molecule
J. Biol. Chem.
(2006) - et al.
Evidence that the cannabinoid CB1 receptor is a 2-arachidonoylglycerol receptor. Structure-activity relationship of 2-arachidonoylglycerol, ether-linked analogues, and related compounds
J. Biol. Chem.
(1999)
Cell adhesion molecules and neuronal regeneration
Curr. Opin. Cell Biol.
The endocannabinoid receptor, CB1, is required for normal axonal growth and fasciculation
Mol. Cell. Neurosci.
Identification of an N-cadherin motif that can interact with the fibroblast growth factor receptor and is required for axonal growth
J. Biol. Chem.
The endocannabinoid system drives neural progenitor proliferation
FASEB J.
Autoradiographic and histological studies of postnatal neurogenesis. IV. Cell proliferation and migration in the anterior forebrain, with special reference to persisting neurogenesis in the olfactory bulb
J. Comp. Neurol.
CAMs and FGF cause a local submembrane calcium signal promoting axon outgrowth without a rise in bulk calcium concentration
Eur. J. Neurosci.
Cannabinoids modulate Olig2 and polysialylated neural cell adhesion molecule expression in the subventricular zone of post-natal rats through cannabinoid receptor 1 and cannabinoid receptor 2
Eur. J. Neurosci.
Therapeutic action of cannabinoids in a murine model of multiple sclerosis
J. Neurosci.
Neuronal replacement from endogenous precursors in the adult brain after stroke
Nat. Med.
Cannabinoid receptor, CB1, expression follows neuronal differentiation in the early chick embryo
J. Anat.
Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain
J. Cell Biol.
Impaired nociception and pain sensation in mice lacking the capsaicin receptor
Science
Niche-independent symmetrical self-renewal of a mammalian tissue stem cell
PLoS Biol.
The effect of neurodegenerative diseases on the subventricular zone
Nat. Rev.
A third-generation lentivirus vector with a conditional packaging system
J. Virol.
Cited by (153)
Perinatal cannabis exposure and long-term consequences on synaptic programming
2022, Cannabis and the Developing BrainCannabinoids
2022, Advances in NeurotoxicologyThe role of lipids in the central nervous system and their pathological implications in amyotrophic lateral sclerosis
2021, Seminars in Cell and Developmental BiologyCannabinoid receptor subtype influence on neuritogenesis in human SH-SY5Y cells
2020, Molecular and Cellular NeuroscienceAntidepressant-like effects of pharmacological inhibition of FAAH activity in socially isolated female rats
2020, European NeuropsychopharmacologyAntidepressant-like effects of β-caryophyllene on restraint plus stress-induced depression
2020, Behavioural Brain Research