Spreading depression requires microglia and is decreased by their M2a polarization from environmental enrichment

Microglia play an important role in fine‐tuning neuronal activity. In part, this involves their production of tumor necrosis factor‐alpha (TNFα), which increases neuronal excitability. Excessive synaptic activity is necessary to initiate spreading depression (SD). Increased microglial production of proinflammatory cytokines promotes initiation of SD, which, when recurrent, may play a role in conversion of episodic to high frequency and chronic migraine. Previous work shows that this potentiation of SD occurs through increased microglial production of TNFα and reactive oxygen species, both of which are associated with an M1‐skewed microglial population. Hence, we explored the role of microglia and their M1 polarization in SD initiation. Selective ablation of microglia from rat hippocampal slice cultures confirmed that microglia are essential for initiation of SD. Application of minocycline to dampen M1 signaling led to increased SD threshold. In addition, we found that SD threshold was increased in rats exposed to environmental enrichment. These rats had increased neocortical levels of interleukin‐11 (IL‐11), which decreases TNFα signaling and polarized microglia to an M2a‐dominant phenotype. M2a microglia reduce proinflammatory signaling and increase production of anti‐inflammatory cytokines, and therefore may protect against SD. Nasal administration of IL‐11 to mimic effects of environmental enrichment likewise increased M2a polarization and increased SD threshold, an effect also seen in vitro. Similarly, application of conditioned medium from M2a polarized primary microglia to slice cultures also increased SD threshold. Thus, microglia and their polarization state play an essential role in SD initiation, and perhaps by extension migraine with aura and migraine. GLIA 2014;62:1176–1194 Main Points: Microglia are necessary to evoke SD. Microglial polarization state (M1 versus M2a) impacts SD threshold. Microglial polarization to an M2a versus M1 dominant phenotype creates an environment of decreased OS that leads to reduced SD. EE promotes an M2a dominant phenotype that reduces susceptibility to SD, an effect that can be mimicked through nasal administration of IL‐11, a cytokine elevated by EE.