Abstract:
Emotions and behavior can be affected by social chemosignals from conspecifics. For instance, olfactory signals from stressed individuals induce stress-like physiological and synaptic changes in naive partners. Direct stress also alters cognition, but the impact of socially transmitted stress on memory processes is currently unknown. Here we show that exposure to chemosignals produced by stressed individuals is sufficient to impair memory retrieval in unstressed male mice. This requires astrocyte control of information in the olfactory bulb mediated by mitochondria-associated CB1 receptors (mtCB1). Targeted genetic manipulations, in vivo Ca(2+) imaging and behavioral analyses reveal that mtCB1-dependent control of mitochondrial Ca(2+) dynamics is necessary to process olfactory information from stressed partners and to define their cognitive consequences. Thus, olfactory bulb astrocytes provide a link between social odors and their behavioral meaning.

Abstract:
Astrocytes control brain activity via both metabolic processes and gliotransmission, but the physiological links between these functions are scantly known. Here we show that endogenous activation of astrocyte type-1 cannabinoid (CB1) receptors determines a shift of glycolysis towards the lactate-dependent production of D-serine, thereby gating synaptic and cognitive functions in male mice. Mutant mice lacking the CB1 receptor gene in astrocytes (GFAP-CB1-KO) are impaired in novel object recognition (NOR) memory. This phenotype is rescued by the gliotransmitter D-serine, by its precursor L-serine, and also by lactate and 3,5-DHBA, an agonist of the lactate receptor HCAR1. Such lactate-dependent effect is abolished when the astrocyte-specific phosphorylated-pathway (PP), which diverts glycolysis towards L-serine synthesis, is blocked. Consistently, lactate and 3,5-DHBA promoted the co-agonist binding site occupancy of CA1 post-synaptic NMDA receptors in hippocampal slices in a PP-dependent manner. Thus, a tight cross-talk between astrocytic energy metabolism and gliotransmission determines synaptic and cognitive processes.

Abstract:
Neurodegenerative disorders are debilitating conditions that impair patient quality of life and that represent heavy social-economic burdens to society. Whereas the root of some of these brain illnesses lies in autosomal inheritance, the origin of most of these neuropathologies is scantly understood. Similarly, the cellular and molecular substrates explaining the progressive loss of brain functions remains to be fully described too. Indeed, the study of brain neurodegeneration has resulted in a complex picture, composed of a myriad of altered processes that include broken brain bioenergetics, widespread neuroinflammation and aberrant activity of signaling pathways. In this context, several lines of research have shown that the endocannabinoid system (ECS) and its main signaling hub, the type-1 cannabinoid (CB1) receptor are altered in diverse neurodegenerative disorders. However, some of these data are conflictive or poorly described. In this review, we summarize the findings about the alterations in ECS and CB1 receptors signaling in three representative brain illnesses, the Alzheimer's, Parkinson's and Huntington's diseases, and we discuss the relevance of these studies in understanding neurodegeneration development and progression, with a special focus on astrocyte function. Noteworthy, the analysis of ECS defects in neurodegeneration warrant much more studies, as our conceptual understanding of ECS function has evolved quickly in the last years, which now include glia cells and the subcellular-specific CB1 receptors signaling as critical players of brain functions.