Endocannabinoid (eCB) signaling has been heavily implicated in the modulation of anxiety, depressive behavior and emotional learning. However, the role of the most abundant body-own cannabinoid, 2-arachidonoylglycerol (2-AG), in the physiological regulation of such affective behaviors is not well understood. We know that a genetic elimination of type 1 cannabinoid receptors (CB1) or the main enzyme involved in 2-AG synthesis, DAGLa, produced profound behavioral changes in animal models of depression. The link between the endocannabinoid system (ECS) and depression was already apparent when the use of rimonabant to treat obesity led to unexpected severe depressive episodes in some patients, which led to the withdrawal of this drug from the market in 2007.
The behavioral effects of eCB signaling have mostly been attributed to neurons, despite the fact that astrocytes, the most abundant glial cell type in the brain, also possess CB1 receptors. In our analyses we thus focused on the possible involvement of astrocytes. Lena-Louise Schüle, Este Leidmaa and colleagues have combined sophisticated genetic, histological and biochemical methods to assess the role of astrocytic DAGLa in 2-AG production in the context of neuropsychiatric disorders.
First, we have shown that DAGLa is present in astrocytes of the adult mouse brain. We saw that astrocytic DAGLa only accounts for a small percentage of the overall brain 2-AG, but this little already contributes to the regulation of healthy affective behaviors. Specifically, it appears to be critically important for maternal care. To come to these conclusions, Lena-Louise Schüle examined genetically altered mice lacking the DAGLa enzyme in astrocytes. Here, female mice without DAGLa having the choice between sugared and pure water drank less of the sweetened water than mice with intact DAGLa. Such a performance is interpreted as anhedonic, depressive-like behavior. We further performed a test that again reflects depressive behavior, and shows how well the dams care for their pups. In this pup retrieval test, the dam has to bring her pups back to the nest within a fixed time period. The test revealed striking effects on maternal behavior, as dams without DAGLa either failed to retrieve their pups to the nest or it took them much longer than unmodified dams. Interestingly, this behavior agreed with elevated levels of sex hormones in mice lacking DAGLa in astrocytes. Our data strongly suggest that minor and cell-specific changes in the ECS can lead to strong changes in behavior that seem to be regulated by female hormones, contributing to the understanding of psychiatric disorders such as depression.
ORIGINAL RESEARCH PAPER
Lena-Louise Schuele, Sandra Glasmacher, Jürg Gertsch, Marie Denise Roggan, Janis-Lisa Transfeld, Laura Bindila, Beat Lutz, Carl-Christian Kolbe, Andras Bilkei-Gorzo, Andreas Zimmer, Este Leidmaa. Diacylglycerol lipase alpha in astrocytes is involved in maternal care and affective behaviors. Glia. 2020 Sep 2. doi: 10.1002/glia.23903. Online ahead of print.