Cellular origin and function of brain 2-arachidonoylglycerol
Molecular Biology and Physiology of Neurons and Glial Cells
Final Report Abstract
The endocannabinoid system is an important modulatory and homeostatic system in the brain. Dysregulations of the endocannabinoid system are involved in affective disorders, such as anxiety-related disorders or major depression. For instance, pharmacological blockade or genetic deletion of the cannabinoid receptor 1 (CB1) increase the incidence and severity of affective disorders. We have shown recently that a deletion of diacylglycerol lipase alpha (Dagla) results in profound changes of anxiety-related and depression-like behaviors in mice. Yet, it is not clear which brain cells produce 2-AG, nor are the physiological effects of 2-AG produced by different cell types known. Thus, in the scope of this project, we generated conditional KO mice with a cell-specific deletion of Dagla in neurons, astrocytes or microglia cells in order to identify the cellular source of 2-AG in the brain and to clarify the role of DAGLa in these cells in affective behaviors. Our main hypothesis was that astrocytes are the main source of brain 2-AG, and that mice with a genetic deletion of Dagla in astrocytes will have reduced levels of 2-AG, in contrast to neuron- or microglia-specific knockouts. As a consequence, we assumed that mice with a lack of astrocytic Dagla display the emotionality phenotype and altered stress-responses that we have observed in constitutive Dagla KO mice. To test this hypothesis, we used a combination of behavioural and molecular studies in mice with a conditional deletion of Dagla in neurons (Syn-Dagla KO mice), microglia (Cx3Cr1-Dagla KO mice ) or astrocytes (GFAP-Dagla KO and GLAST-CreERT2-Dagla KO mice). Our data demonstrates that Dagla is expressed in a subpopulation of astrocytes and that Dagla expression in astrocytes is generally lower than in neurons. Thus, our main hypothesis that astrocytes are the main source of brain 2-AG was wrong, because we did not know that the expression of GFAP-Cre was leaky and that the synapsin promoter is not expressed in all neurons. Although astrocytic DAGLa only accounts for a minor fraction of overall brain 2-AG levels and specific deletion of Dagla in astrocytes lead only to small changes in the arachidonate lipid network, it nevertheless constitutes a hitherto unknown metabolic axis in the endocannabinoid system. Our data strongly suggest that minor and cell-specific changes in the extended endocannabinoid system can lead to strong behavioural effects. Moreover, these seem to be regulated by female hormones.
Publications
-
(2020) Diacylglycerol lipase alpha in astrocytes is involved in maternal care and affective behaviors. Glia. 2020 Sep 2
Schuele LL, Glasmacher S, Gertsch J, Roggan MD, Transfeld JL, Bindila L, Lutz B, Kolbe CC, Bilkei-Gorzo A, Zimmer A, Leidmaa E
