Disruption of theATP/adenosine balance inCD39^−/−mice is associated with handling‐induced seizures

Abstract

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 for CD39, a cell-surface ATPase 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 of CD39 mice contained increased levels of ATP and 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. Systemic LPS challenge 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 in CD39 versus CD39 mice. However, LPS treatment did not affect handling-induced seizures. In addition, microglia-specific CD39 deletion in adult mice was not sufficient to cause seizures, suggesting instead that altered expression of CD39 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 extracellular ATP/adenosine ratio and a previously unreported seizure phenotype in CD39 mice. This work provides groundwork for further elucidation of the underlying mechanisms of epilepsy.

Effects of the ecto-ATPase apyrase on microglial ramification and surveillance reflect cell depolarization, not ATP depletion

“…However, in these studies NTPDase1 was globally knocked-out and the effects on microglial morphology of a direct, pharmacological inhibition or microglial-specific knockout were not tested. This is important, since NTPDase1-mediated effects can also originate from other cells (47). NTPDase1 is also prominently expressed at the surface of vascular smooth muscle cells (18,40), where it contributes to the regulation of vascular tone and A key outcome of our study is that, surprisingly, all apyrase preparations that we tested, Apyrase is commonly used in neurobiological studies due to the widespread role of ATP as a neurotransmitter (58).…”

P2X7 Receptors Amplify CNS Damage in Neurodegenerative Diseases

“…NTPDase1 hydrolyses nucleoside 5′-triphosphates and -diphosphates equally well and is the main ATP degrading enzyme in microglia [ 92 ]. NTPDase1-deficient (CD39 −/− ) mice, due to less enzymatic degradation of ATP, exhibited increased levels of ATP and decreased levels of adenosine in their cerebrospinal fluid [ 93 ]. In addition, they were prone to handling-induced and spontaneous epileptic seizures [ 93 ].…”

“…NTPDase1-deficient (CD39 −/− ) mice, due to less enzymatic degradation of ATP, exhibited increased levels of ATP and decreased levels of adenosine in their cerebrospinal fluid [ 93 ]. In addition, they were prone to handling-induced and spontaneous epileptic seizures [ 93 ]. HPLC measurements of ATP and its metabolites (ADP, AMP, adenosine) only partially supported this hypothesis, because during pilocarpine-induced temporal lobe epilepsy the extracellular ATP concentrations showed only a tendency to be increased in the microdialysate of the hippocampus [ 94 ].…”

Novel Players in the Aging Synapse: Impact on Cognition

“…167 Alonso-Andrés et al showed that adenosine is the most affected purine in AD, being decreased since early stage, 167 possibly as a result of a decrease in 5¢-nucleotidases. 170 Adenosine augmentation has been found beneficial in multiple neurological disorders, including AD. 171,172 However, further comprehension of the mechanism and the putative effects on adenosine receptors and downstream signaling pathways are crucial at this stage.…”