Diacylglycerol Lipase-β Knockout Mice Display a Sex-Dependent Attenuation of Traumatic Brain Injury-Induced Mortality with No Impact on Memory or Other Functional Consequences

Abstract

Background: The endogenous cannabinoid system modulates inflammatory signaling in a variety of pathological states, including traumatic brain injury (TBI). The selective expression of diacylglycerol lipase-b (DAGL-b), the 2-arachidonylglycerol biosynthetic enzyme, on resident immune cells of the brain (microglia) and the role of this pathway in neuroinflammation, suggest that this enzyme may contribute to TBI-induced neuroinflammation. Accordingly, we tested whether DAGL-b À/À mice would show a protective phenotype from the deleterious consequences of TBI on cognitive and neurological motor functions. Materials and Methods: DAGL-b À/À and -b + / + mice were subjected to the lateral fluid percussion model of TBI and assessed for learning and memory in the Morris water maze (MWM) Fixed Platform (reference memory) and Reversal (cognitive flexibility) tasks, as well as in a cued MWM task to infer potential sensorimotor/motivational deficits. In addition, subjects were assessed for motor behavior (Rotarod and the Neurological Severity Score assays) and in the light/dark box and the elevated plus maze to infer whether these manipulations affected anxietylike behavior. Finally, we also examined whether brain injury disrupts the ceramide/sphingolipid lipid signaling system and if DAGL-b deletion offers protection. Results: TBI disrupted all measures of neurological motor function and reduced body weight, but did not affect body temperature or performance in common assays used to infer anxiety. TBI also impaired performance in MWM Fixed Platform and Reversal tasks, but did not affect cued MWM performance. Although no differences were found between DAGL-b À/À and -b + / + mice in any of these measures, male DAGL-b À/À mice displayed an unexpected survival-protective phenotype, which persisted at increased injury severities. In contrast, TBI did not elicit mortality in female mice regardless of genotype. TBI also produced significant changes in sphingolipid profiles (a family of lipids, members of which have been linked to both apoptotic and antiapoptotic pathways), in which DAGL-b deletion modestly altered levels of select species. Conclusions: These findings indicate that although DAGL-b does not play a necessary role in TBI-induced cognitive and neurological function, it appears to contribute to the increased vulnerability of male mice to TBIinduced mortality, whereas female mice show high survival rates irrespective of DAGL-b expression.

The Novel Monoacylglycerol Lipase Inhibitor MJN110 Suppresses Neuroinflammation, Normalizes Synaptic Composition and Improves Behavioral Performance in the Repetitive Traumatic Brain Injury Mouse Model

“…Consistently, the dual DAGLα and DAGLβ inhibitor DO34 reversed LPS-induced allodynia in mice with DAGLα deletion but had no effect on the antinociceptive effect of DAGLβ knockout mice [ 87 ]. Interestingly, a recent study showed that DAGLβ knockout male mice are resistant to TBI-induced mortality, but had no effect on motor and cognitive function, suggesting that blockade of AA and the subsequent prostaglandin production in reactive microglia/macrophages by targeting DAGLβ is unable to exert neuroprotective effects [ 88 ]. In our current study, treatment with DO34 significantly reduced the brain levels of 2-AG, AA and PGE 2 , and reversed the MJN110 mediated beneficial effects in the TBI animals.…”

Imaging and Genetic Tools for the Investigation of the Endocannabinoid System in the CNS

“…GFAP:MAGL −/− Reduced neuroinflammation independent of CB1R and total 2-AG [281] DAGLα −/− Gao No effect on pain sensitization [312] DAGLβ-GT Lex ; gene trap Reduced pain sensitization [312] Parkinson's disease MAGL-GT Lex ; gene trap Reduced neuroinflammation; neuroprotection; prostaglandin and not ECS related [32] DAGLβ-GT Lex ; gene trap DAGLβ is main 2-AG synthesizer in SN 6 ; contributes to disease progression in mice and rare-variant patients [313] Stress + anxiety DAGLα fl/fl Decreased stress resilience (BLA 7 AAV 8 -directed) [264] DAGLα fl/fl Reduced stress behaviour [314] DAGLα −/− Increased anxiety; anhedonia [262] DAGLα −/− Increased fear, anxiety; loss of maternal care [263] FAAH −/− Reduced anxiety [315] Substance use disorders FAAH −/− Increased ethanol consumption and preference [316] FAAH −/− Increased alcohol sensitivity and withdrawal [317] FAAH −/− Reduced morphine withdrawal [318] TBI 9 DAGLβ-GT Lex ; gene trap Sex-dependant increase in survival; attenuated sphingolipid TBI 9 markers [319] GFAP:MAGL flox/flox Reduced neuroinflammation, neuroprotection, CB1R-PPARγ-dependent [320] ALS 1 : amyotrophic lateral sclerosis; EAE 2 : experimental autoimmune encephalomyelitis; MS 3 : multiple sclerosis; DSI 4 : depolarization-induced suppression of inhibition; LPS 5 : lipopolysaccharides; SN 6 : substantia nigra; BLA 7 : basolateral amygdala; AAV 8 : adeno-associated virus; TBI 9 : traumatic brain injury.…”