Abstract
The endocannabinoid system modulates adult hippocampal neurogenesis by promoting the proliferation and survival of neural stem and progenitor cells (NSPCs). This is demonstrated by the disruption of adult neurogenesis under two experimental conditions: (1) NSPC-specific deletion of cannabinoid receptors and (2) constitutive deletion of the enzyme diacylglycerol lipase alpha (DAGLa) which produces the endocannabinoid 2-arachidonoylglycerol (2-AG). However, the specific cell types producing 2-AG relevant to neurogenesis remain unknown. Here we sought to identify the cellular source of endocannabinoids in the subgranular zone of the dentate gyrus (DG) in hippocampus, an important neurogenic niche. For this purpose, we used two complementary Cre-deleter mouse strains to delete Dagla either in neurons, or in astroglia and NSPCs. Surprisingly, neurogenesis was not altered in mice bearing a deletion of Dagla in neurons (Syn-Dagla KO), although neurons are the main source for the endocannabinoids in the brain. In contrast, a specific inducible deletion of Dagla in NPSCs and astrocytes (GLAST-CreERT2-Dagla KO) resulted in a strongly impaired neurogenesis with a 50% decrease in proliferation of newborn cells. These results identify Dagla in NSPCs in the DG or in astrocytes as a prominent regulator of adult hippocampal neurogenesis. We also show a reduction of Daglb expression in GLAST-CreERT2-Dagla KO mice, which may have contributed to the neurogenesis phenotype.
Highlights
Adult neurogenesis is a process in which new neurons are continuously generated in the adult mammalian brain[1]
In this study we show that the endocannabinoid 2-AG producing enzyme diacylglycerol lipase alpha (DAGLa) is expressed in neural stem and progenitor cells (NSPCs) of the hippocampal dentate gyrus (DG) region, albeit at lower levels compared to neurons in the granule cell layer
Deleting DAGLa from NSPCs was important for the regulation of adult hippocampal neurogenesis, whereas deletion of neuronal diacylglycerol lipase alpha (Dagla) did not affect neurogenesis
Summary
Adult neurogenesis is a process in which new neurons are continuously generated in the adult mammalian brain[1]. Even though the biological role of adult neurogenesis is far from being fully elucidated, it is well established that new adult-born neurons from SVZ and SGZ are functionally incorporated in the olfactory bulb or hippocampus, respectively, participating in the function of this areas[2]. Several studies revealed that endocannabinoid signaling plays a crucial role in the regulation of proliferation, differentiation and survival of progenitor cells in the neurogenic niches. The cell type that regulates adult neurogenesis by endocannabinoids is not yet identified. Regarding CB1 signaling, a very recent study found that deleting CB1 in NSPCs using an inducible Nestin-CreERT2 strain was sufficient to lead to reduced proliferation of progenitors in the DG of adult mice. Conditional Dagla KO mice with a deletion in either neurons or astrocytes and NSPCs were used
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