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

Abstract

Microglia are highly dynamic immune cells of the CNS and their dynamism is proposed to be regulated by neuronal activities. However, the mechanisms underlying neuronal regulation of microglial dynamism have not been determined. Here, we found an increased number of microglial primary processes in the hippocampus during KA-induced seizure activity. Consistently, global glutamate induced robust microglial process extension toward neurons in both brain slices and in the intact brain in vivo. The mechanism of the glutamate-induced microglial process extension involves the activation of neuronal NMDA receptors, calcium influx, subsequent ATP release, and microglial response through P2Y12 receptors. Seizure-induced increases in microglial process numbers were also dependent on NMDA receptor activation. Finally, we found that P2Y12 KO mice exhibited reduced seizure-induced increases in microglial process numbers and worsened KA-induced seizure behaviors. Our results elucidate the molecular mechanisms underlying microglia-neuron communication that may be potentially neuroprotective in the epileptic brain.

Purinergic mechanisms in neuroinflammation: An update from molecules to behavior

“…For example, during epileptic seizures, excess glutamate is released, which promotes microglial process extension towards the site of damage. This process involves the activation of neuronal NMDA receptors, calcium influx, subsequent ATP release, and the activation of P2Y 12 receptors (Eyo et al, 2014). A similar phenomenon, described recently and termed microglial process convergence (MPC) involves the convergence of microglial processes on neuronal dendrites in response to a reduction of extracellular Ca 2þ (Eyo et al, 2015).…”

Microglia in steady state

“…It was also shown that microglial cells make direct contact with pre-and postsynaptic structures, and these cells have been seen to continuously interact for 4-5 minutes in the healthy CNS (63). However, this contact is greatly prolonged during the status epilepticus in the ischemic CNS (63), and neuronal hyperactivity results in an increase in microglial processes that are recruited toward the active synapse (64). One can conclude from these and other studies that microglia seem to sense synaptic activity, prolong their contact with actively signaling synapses, and also modulate the neuronal activity at the synapse (63-65).…”

Coupled Oscillators Model of Hyperexcitable Neuroglial Networks

“…There is evidence that they are neuroprotective early in acute seizures [69]. Eyo et al reported increased microglial contact with neuronal elements that when blocked resulted in a worsened seizure phenotype [81]. Furthermore, Derecki et al found that blocking microglial phagocytosis promotes the development of Rett Syndrome, a condition that most often results in seizures [82].…”