An important component of neurodegenerative disorders, like Alzheimer’s disease (AD), is the prolonged inflammatory response driven by continuous microglial poly (ADP-ribose) polymerase-1 (PARP-1) activation. However, mechanisms that promote sustained microglial PARP-1 activation and maintaining microglial activity remains elusive. But we know that PARP-1 enzymatic activity requires Ca2+ influx, a process that is independent of DNA damage, and this could be through microglial N-methyl D-aspartate receptors (NMDARs). Notably, PARP-1 mediated ADP-ribose production causes activation of Ca2+ permeable non-selective cation channel, transient receptor potential melastatin-2 (TRPM2). Hence, we hypothesize that NMDAR activation by amyloid beta oligomers (AβO) or NMDA initiates PARP-1 mediated ADPR production and TRPM2 activation. This in-turn leads to TRPM2-dependent, self-sustaining PARP-1 activation, which promotes pro-inflammatory responses. Primary microglia treated with AβO and NMDA were assessed for functional TRPM2 currents using whole cell voltage-clamp electrophysiology. Using nitric oxide assay and qRT-PCR, AβO/NMDA treated microglia were also evaluated to identify the contribution of NMDAR/PARP-1/TRPM2 in promoting pro-inflammatory responses. Our findings, demonstrates that glutamate signaling via NMDARs, promoting detrimental microglial responses, suggests a unifying mechanism linking elevated glutamate levels, associated for example with AD, hypoxic-ischemic injury, or traumatic brain injury, to chronic neuroinflammation.