The molecular organization of 2-arachidonoylglycerol signalling during brain development

• Main Author: Keimpema, Erik
• Published: University of Aberdeen 2011
• Subjects: 612.8
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.542632

Endocannabinoids (eCBs) regulate a broad range of physiological functions in the postnatal brain and are implicated in the neuropathogenesis of psychiatric and metabolic diseases. Accumulating evidence indicates that eCB signalling, particularly 2-arachidonoyglycerol (2-AG), also serves key functions during neurodevelopment. This study investigated <i>1)</i> the role of CB₁ cannabinoid receptor (CB₁R) signalling during pyramidal and cholinergic cell development, <i>2)</i> the molecular distribution and subcellular organization of the 2-AG metabolic enzymes in pyramidal- and cholinergic neurons and <i>3)</i> the control of the 2-AG signalling cassette by nerve growth factor (NGF) in developing cholinergic neurons. Similar to the distribution of the CB₁R, sn-1-diacylglycerol lipase α (DAGLα), synthesizing 2-AG, was localized to growth cones and axons of growing pyramidal and cholinergic neurons. In contrast, monoacylglycerol lipase (MGL), degrading 2-AG, was preferentially targeted to the stabilized axon stem and was rapidly degraded by the proteasome in moving growth cones. Upon target innervation, DAGLα was restricted to postsynaptic dendritic sites while MGL appeared in the growth cone upon formation of the presynapse. In cholinergic neurons, NGF up-regulated the expression of the 2-AG signalling cassette together with the breast cancer type 1 susceptibility protein (BRCA1) whose E3 ubiquitin ligase activity augments the degradation of MGL in motile axonal tips, increasing 2-AG availability. Summarizing, this study demonstrates the diverse involvement of 2-AG-mediated CB₁R signalling in neuronal proliferation, migration and axonal outgrowth during brain development.