Abstract

Microglia are the resident immune cells of the central nervous system (CNS). In healthy conditions, they survey the CNS contributing to physiological functions, such as the support of neurogenesis and the pruning of synaptic spines. In pathological conditions, they are activated by inflammatory stimuli and mediate several aspects of the immune response. In both scenarios, microglia sense the surrounding environment and their functions are controlled by a plethora of pathways involving cell-cell contacts and paracrine modulation. Among these, we focused on two monoamines, noradrenaline and serotonin (5-HT) and their capacity to regulate the microglia activity in health and pathology. In preliminary work here presented, we questioned the role of monoaminergic modulation of microglia, using in vitro models involving cultured cells, calcium imaging, migration assays, and flow cytometry assays. By these means, we measured the responsiveness of microglia to monoamines in resting and activated states, as well as the effects of monoaminergic stimulation in relation to microglia motility and activation. We found that noradrenergic and serotoninergic stimulation of resting microglia triggered intracellular calcium signaling. However, the responses elicited by noradrenaline were more prominent than those elicited by 5-HT. Moreover, the activation of microglia by lipopolysaccharides (LPS) led to significantly increased sensitivity to noradrenaline, but not to 5-HT. In relation to cell motility, noradrenaline and 5-HT did not significantly affect the rate of microglia migration towards ATP, used as chemoattractant. However, noradrenaline significantly increased the rate of microglia migration towards LPS, used as chemoattractant, whereas 5-HT did not. Furthermore, in relation to microglia activation induced by LPS, both noradrenaline and 5-HT significantly decreased the expression of the activation marker CD40. Therefore, our data imply the relevance of monoamines as microglia modulators, which role changes from physiological to pathological conditions. Since monoaminergic neurotransmission is altered in several CNS pathologies, it will be interesting to determine which symptoms relate to altered neuromodulation directly, and which relate to altered microglia modulation dependent on their pro-inflammatory state.