Status Epilepticus Induces a Particular Microglial Activation State Characterized by Enhanced Purinergic Signaling

Abstract

Microglia cells are the resident macrophages of the CNS, and their activation plays a critical role in inflammatory reactions associated with many brain disorders, including ischemia, Alzheimer's and Parkinson's diseases, and epilepsy. However, the changes of microglia functional properties in epilepsy have rarely been studied. Here, we used a model of status epilepticus (SE) induced by intraperitoneal kainate injections to characterize the properties of microglial cells in hippocampal slices from CX3CR1 eGFP/ϩ mice. SE induced within 3 h an increased expression of inflammatory mediators in the hippocampus, followed by a modification of microglia morphology, a microglia proliferation, and a significant neurodegeneration in CA1. Changes in electrophysiological intrinsic membrane properties of hippocampal microglia were detected at 24 -48 h after SE with, in particular, the appearance of new voltage-activated potassium currents. Consistent with the observation of an upregulation of purinergic receptor mRNAs in the hippocampus, we also provide pharmacological evidence that microglia membrane currents mediated by the activation of P2 receptors, including P2X 7 , P2Y 6 , and P2Y 12 , were increased 48 h after SE. As a functional consequence of this modification of purinergic signaling, motility of microglia processes toward a source of P2Y 12 receptor agonist was twice as fast in the epileptic hippocampus. This study is the first functional description of microglia activation in an in vivo model of inflammation and provides evidence for the existence of a particular microglial activation state after a status epilepticus.

Neuronal Hyperactivity Recruits Microglial Processes via Neuronal NMDA Receptors and Microglial P2Y12 Receptors after Status Epilepticus

“…The 4-to 6-week-old heterozygous GFP reporter mice (CX3CR1 GFP/ϩ ) were intraperitoneally or intracerebroventricularly injected with KA at 18 -22 mg/kg or 0.12-0.18 g in 5 l of ACSF, respectively. Seizure behavior was monitored under a modified Racine scale as follows: (1) freezing behavior; (2) rigid posture with raised tail; (3) continuous head bobbing and forepaws shaking; (4) rearing, falling, and jumping; (5) continuous level 4; and (6) loss of posture and generalized convulsion activity (Racine, 1972;Avignone et al, 2008). Mice progressed at least to stage 3 and were killed at 45 min and microglial morphology in the CA1 was analyzed.…”

New insights regarding the regulation of chemotaxis by nucleotides, adenosine, and their receptors

“…Altered expression of the key receptors in this process during states of microglial activity (e.g., upregulation of inhibitory receptors and downregulation of stimulatory receptors upon microglial activation) may help fine-tune potentially catastrophic inflammatory responses in the CNS. Indeed, enhancement in P2-mediated signalling and migration responses has been observed in microglia in a mouse model of status epilepticus [69].…”

“…Considerable evidence implicates P1/P2-mediated cell migration pathways in pathophysiology [69]. For example, recent studies show that pathogens such as HIV [110] and malaria [111] promote infection by "hijacking" P1/P2 signaling pathways.…”

Perspectives of purinergic signaling in stem cell differentiation and tissue regeneration

“…In view of that, purinergic receptor antagonists should offer a novel treatment for blocking Ca 2+ wave propagation stimulated by ATP [93]. As further proof for such mechanism, injection of high doses of ATP into rat cortex promoted an increase in seizure occurrence, which could be antagonized by suramin [94]. Hippocampi from chronic epileptic rats demonstrated elevated P2X7 receptor expression and abnormal responses to ATP, suggesting a possible participation of this system in the pathophysiology of epilepsy [95].…”