Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a selective loss of motor neurons (MN). During ALS, ATP released by neurons and glial cells modulates the neuroglial interplay via activation of P2X receptors. Among these, P2X4 receptor, which is a non-selective cationic channel, has been recently involved in ALS pathogenesis. We found that both the absence of P2X4 or the increase of surface P2X4 using P2X4KO or non-internalized P2X4KI mice respectively, have a beneficial outcome in the SOD1 mice. This paradoxical output suggests a complex cell-role of P2X4 in ALS, so far unexplored. To address the neuroglial role of P2X4 in ALS, we have developed triple transgenic SOD1 mice, inducing either an increase in surface P2X4 or a deletion of P2X4 gene selectively in microglia/macrophages or neurons. Our results show that the neuronal increase of P2X4 accelerates ALS progression, spinal MN degeneration and mouse death while increase of P2X4 at the surface of microglia/macrophages has a positive impact on the progression of the disease. We are currently studying morphological and functional changes in microglia from these lines which may support neuronal viability through ALS progression. Altogether, dual roles of P2X4 may be involved on the neuroimmune crosstalk occurring during ALS. Further studies need to be carried to better understand the contribution of P2X4 in the interplay between MN death and microglia reactivity over the disease progression, providing valuable insights into the cellular role of P2X4 to fight ALS.