Fig. 5
The potential function of microglia in sensing and regulating UMN hyperexcitability in ALS. Representation of microglia-neuron interaction in ALS. A Microglia may sense upper motor neuron (UMN) hyperexcitability through ATP and purinergic signaling. Hyperactivated motor neurons release ATP into the extracellular space through channel-mediated release mechanisms [such as volume-activated anion channels (VAAC), P2X7 receptors, and Pannexin 1 channels (Panx1)] or through Ca.2+-dependent vesicular release mechanism. Extracellular ATP is then hydrolyzed into ADP and sensed by P2Y12 receptors, recruiting microglia processes towards this ATP source. B Activated microglia interact with dendritic spines and trigger synaptic pruning. The molecular components involved in synaptic pruning may include complement proteins (such as C3/CR3), CX3CL1/CX3CR1 and TREM2/lipid phosphatidylserine (PS). C Activated microglia contact neuronal dendrites or somatic membranes at Kv2.1/2.2 clustering through microglial P2Y12 receptor to for purinergic junctions. D Microglia interact with the axon initial segment to regulate action potential generation through mechanisms that are currently unknown. E Extracellular ATP can be converted to AMP by the microglial ATP/ADP-hydrolyzing ectoenzyme CD39. AMP can then be used as a substrate for the microglial enzyme CD73 to generate adenosine (ADO), which can suppress neuronal activity by binding to adenosine A1 receptors (A1Rs)