Anales RANF

CPL-02 PURINERGIC SIGNALING IN MICROGLIAL FUNCTIONS Kazuhide Inoue. Kyushu University, Fukuoka, Japan Microglia are thought to derive from primitive macrophages in the yolk sac. In normal, microglia are ubiquitously distributed throughout central nervous system (CNS) and have small cell body bearing branched and motile processes. In response to peripheral nerve injury (PNI), microglia are activated with hypertrophic morphology, an increase in cell number, and alteration in the expression of genes including neurotransmitter receptors such as purinergic P2 receptors in the spinal cord (Tsuda et al 2005). Extracellular ATP activate microglia to evoke various cellular responses such as the production and release of bioactive factors including cytokines and neurotrophic factors (Inoue 2006), which in turn leads neuropathic pain (Tsuda et al 2012)and several diseases in CNS. Neuropathic pain is a debilitating pain state, which is often caused by physical injury, diabetes, bone compression in cancer. One of the symptoms of neuropathic pain is tactile allodynia (strong pain by light touching) which is not healed by non-steroidal anti-inflammatory drugs and opioids. We found that activated microglia of spinal dorsal horn (SDH) over- expressed P2X4 receptors which cause to release brain-derived neurotrophic factor (BDNF) after the stimulation of ATP. BDNF causes downregulation of the chloride transporter KCC2 in a subpopulation of lamina I secondary sensory neurons in SDH, which then causes a depolarizing shift in the anion reversal potential. This shift inverts the polarity of currents activated by γ -amino butyric acid (GABA) and glycine, such that GABA and glycine cause depolarization, rather than hyperpolarization, in these secondary sensory neurons resulting in tactile allodynia (Nature, 2003, Nature, 2005). This finding is a breakthrough for this science area and many papers were reported after the breakthrough (Nat Commun. 2014, Nat Commun. 2016, Nature Review Neuroscience 2018). Now, we know that the purinergic signaling of microglia play main roles of CNS diseases.