Modulating the reactive phenotype of astrocytes as a therapeutic approach in amyotrophic lateral sclerosis

Several causes have been suggested to contribute to amyotrophic lateral sclerosis (ALS) aetiology and glutamate (Glu)-mediated excitotoxicity plays a major role. Besides motor neuron (MN) death, also non-neuronal cells, such as astrocytes and microglia, undergo degeneration and functional alterations. Thus, a precise modulation of each cell population it might be crucial to design an effective therapy. Group I metabotropic Glu receptors (mGluR1/5) play a role in ALS, since their expression and functions, are dramatically altered, especially in glial cells. In this contest, we showed that group I mGluRs sustains the excessive Glu release in the spinal cord of the SOD1G93A mouse model of ALS and this alteration is already present at the onset of the pathology. Most importantly, the in-vivo mGluR1/5 knock-down or the mGluR5 pharmacological blockade with CTEP, significantly prolongs survival probability and ameliorates the clinical progression of the disease in SOD1G93A mice. These effects are always associated with spinal MN preservation, decreased astrocyte and microglia activation and reduced Glu release, in the spinal cord of SOD1G93A mice. We then investigated the effect of mGluR5 genetic downregulation (mgluR5+/-), on the reactive phenotype of spinal cord astrocytes cultured from symptomatic SOD1G93A mice. Our results showed that the elevated cytosolic Ca2+ concentration as well as the over expression of specific markers of astrocyte activation (GFAP, S100, Vimentin) were significantly reduced in spinal cord SOD1G93A_mGluR5+/- astrocytes. Of note, the modulation of the reactive phenotype by mGluR5 downregulation translates into a reduced release of neuroinflammatory cytokines (IL1b, IL-6, TNFa), improved bioenergetics and a less toxic effect of astrocytes toward co-cultured MNs. We conclude that a lower constitutive level of mGluR5 has positive effects on spinal cord SOD1G93A astrocytes, supporting the role of mGluR5 as a therapeutic target to obtain a shift from pathological to a less noxious phenotype of reactive astrocytes in ALS.