Hashem, J. | bioRxiv Science

bioRxiv2024

Overabundant endocannabinoids in neurons are detrimental to cognitive function

2-Arachidonoylglycerol (2-AG) is the most prevalent endocannabinoid involved in maintaining brain homeostasis. Previous studies have demonstrated that inactivating monoacylglycerol lipase (MAGL), the primary enzyme responsible for degrading 2-AG in the brain, alleviates neuropathology and prevents synaptic and cognitive decline in animal models of neurodegenerative diseases. However, we show that selectively inhibiting 2-AG metabolism in neurons impairs cognitive function in mice. This cognitive impairment appears to result from decreased expression of synaptic proteins and synapse numbers, impaired long-term synaptic plasticity and cortical circuit functional connectivity, and diminished neurogenesis. Interestingly, the synaptic and cognitive deficits induced by neuronal MAGL inactivation can be counterbalanced by inhibiting astrocytic 2-AG metabolism. Transcriptomic analyses reveal that inhibiting neuronal 2-AG degradation leads to widespread changes in expression of genes associated with synaptic function. These findings suggest that crosstalk in 2-AG signaling between astrocytes and neurons is crucial for maintaining synaptic and cognitive functions and that excessive 2-AG in neurons alone is detrimental to cognitive function.

neuroscience↗

bioRxiv2021

Adar1 deletion causes degeneration of exocrine pancreas via Mavs-dependent interferon signaling

Adenosine deaminase acting on RNA 1 (ADAR1) is an RNA-binding protein that deaminates adenosine(A) to inosine(I). A-to-I editing alters post-transcriptional RNA processing making ADAR1 a critical regulator of gene expression. Consequently, Adar1 has been implicated in organogenesis. To determine the role of Adar1 in pancreatic development and homeostasis, we specifically deleted Adar1 from the murine pancreas (Ptf1aCre/+; Adar1Fl/Fl). The resulting mice had stunted growth likely due to malabsorption associated with exocrine pancreas insufficiency. Analyses of pancreases revealed ductal expansion, heightened interferon-stimulated gene expression and an increased influx of immune cells. In addition, we observed an increased prevalence of CD4+ T and natural killer cells in their splenic tissue. These results indicate an association between loss of pancreatic Adar1 with dysregulation of systemic immunity. Concurrent deletion of Adar1 and Mavs, a signaling protein implicated in the innate immune pathway rescued the degenerative phenotype and resulted in normal pancreatic development. Taken together, our work suggests that the primary function of Adar1 in the pancreas is to prevent aberrant activation of the Mavs-mediated innate immune pathway, thereby maintaining pancreatic homeostasis. Summary statementThis work defines the role of Adar1 in pancreatic development and homeostasis.

developmental biology↗