Disruption of the ATP /adenosine balance in CD 39−/−mice is associated with handling‐induced seizures

Summary Seizures are due to excessive, synchronous neuronal firing in the brain and are characteristic of epilepsy, the fourth most prevalent neurological disease. We report handling‐induced and spontaneous seizures in mice deficient forCD39, a cell‐surfaceATPase highly expressed on microglial cells.CD39−/−mice with handling‐induced seizures had normal input–output curves and paired‐pulse ratio measured from hippocampal slices and lacked microgliosis, astrogliosis or overt cell loss in the hippocampus and cortex. As expected, however, the cerebrospinal fluid ofCD39−/−mice contained increased levels ofATPand decreased levels of adenosine. To determine if immune activation was involved in seizure progression, we challenged mice with lipopolysaccharide (LPS) and measured the effect on microglia activation and seizure severity. SystemicLPSchallenge resulted in increased cortical staining of Iba1/CD68 and gene array data from purified microglia predicted increased expression of interleukin‐8, triggering receptor expressed on myeloid cells 1, p38, pattern recognition receptors, death receptor, nuclear factor‐κB , complement, acute phase, and interleukin‐6 signalling pathways inCD39−/−versusCD39+/+mice. However,LPStreatment did not affect handling‐induced seizures. In addition, microglia‐specificCD39 deletion in adult mice was not sufficient to cause seizures, suggesting instead that altered expression ofCD39 during development or on non‐microglial cells such as vascular endothelial cells may promote the seizure phenotype. In summary, we show a correlation between altered extracellularATP/adenosine ratio and a previously unreported seizure phenotype inCD39−/−mice. This work provides groundwork for further elucidation of the underlying mechanisms of epilepsy.