The GluN2A Subunit Regulates Neuronal NMDA receptor-Induced Microglia-Neuron Physical Interactions

Abstract

Microglia are known to engage in physical interactions with neurons. However, our understanding of the detailed mechanistic regulation of microglia-neuron interactions is incomplete. Here, using high resolution two photon imaging, we investigated the regulation of NMDA receptor-induced microglia-neuron physical interactions. We found that the GluN2A inhibitor NVPAAM007, but not the GluN2B inhibitor ifenprodil, blocked the occurrence of these interactions. Consistent with the well-known developmental regulation of the GluN2A subunit, these interactions are absent in neonatal tissues. Furthermore, consistent with a preferential synaptic localization of GluN2A subunits, there is a differential sensitivity of their occurrence between denser (stratum radiatum) and less dense (stratum pyramidale) synaptic sub-regions of the CA1. Finally, consistent with differentially expressed GluN2A subunits in the CA1 and DG areas of the hippocampus, these interactions could not be elicited in the DG despite robust microglial chemotactic capabilities. Together, these results enhance our understanding of the mechanistic regulation of NMDA receptor-dependent microglia-neuronal physical interactions phenomena by the GluN2A subunit that may be relevant in the mammalian brain during heightened glutamatergic neurotransmission such as epilepsy and ischemic stroke.

Microglial proliferation and monocyte infiltration contribute to microgliosis following status epilepticus

“…This discrepancy may be due to the differential response of microglia in CA1 (Avignone et al, ) versus CA3 (our investigation) regions of the hippocampus after KA‐induced seizures. Consistently, we noted regional difference of microglial response to NMDA‐induced neuronal hyperactivities in mouse hippocampus (Eyo et al, ). In addition, we noted an increase in expression of P2Y12 in the CA1, whereas the expression was downregulated in the CA3 after KA induced seizures (data not shown).…”

A decade of diverse microglial-neuronal physical interactions in the brain (2008–2018)

“…In addition, a different phenomenon (where microglial processes converged focally to dendritic hotspots, rather than radiating outward on neuronal dendrites) was discovered following global glutamatergic activation or kainic acid induced seizures [16]. Both phenomena depend specifically on the GluN2a NMDAR subunit [13]. Knocking out P2Y12Rs abolished both phenomena and corresponded with increased seizure intensities [16,17] suggesting that these interactions may serve to downregulate neuronal activity.…”

“…In a narrow window between P8 and P10, microglia frequently induced filopodia, precursors to spines, on dendritic shafts in a contact-dependent manner. Moreover, microglial depletion correlated with reduced spine densities and reduced functional synapses suggesting that microglia promote synaptogenesis in the developing cortex [13]. Interestingly, microglia promote learning-dependent synapse formation in adults in a brain derived neurotrophic factor (BDNF)-dependent manner [43].…”

Environmental Signals on Microglial Function during Brain Development, Neuroplasticity, and Disease

“…Whole-cell patch clamp experiments have demonstrated that the activation of dendritic NMDA receptors in a single neuron is enough to trigger the growth of microglial extensions, establishing a direct link between neuronal activity and microglial dynamics. In relation to the mechanisms involved in this physical interaction, mediated by electrical activity between microglia and neurons, it has been established that this regulation is mediated by the GluN2A subunit of the NMDA receptor [20]. Besides that, microglia shift from different stages of activation also depends on a cross-talk between neurons, astrocytes, and microglial cells, which is essential for adaptive neuroplasticity.…”