Microglial displacement of inhibitory synapses provides neuroprotection in the adult brain

Abstract

Microglia actively survey the brain microenvironment and play essential roles in sculpting synaptic connections during brain development. While microglial functions in the adult brain are less clear, activated microglia can closely appose neuronal cell bodies and displace axosomatic presynaptic terminals. Microglia-mediated stripping of presynaptic terminals is considered neuroprotective, but the cellular and molecular mechanisms are poorly defined. Using 3D electron microscopy, we demonstrate that activated microglia displace inhibitory presynaptic terminals from cortical neurons in adult mice. Electrophysiological recordings further establish that the reduction in inhibitory GABAergic synapses increased synchronized firing of cortical neurons in γ-frequency band. Increased neuronal activity results in the calcium-mediated activation of CaM kinase IV, phosphorylation of CREB, increased expression of antiapoptotic and neurotrophic molecules and reduced apoptosis of cortical neurons following injury. These results indicate that activated microglia can protect the adult brain by migrating to inhibitory synapses and displacing them from cortical neurons.

PreImplantation Factor bolsters neuroprotection via modulating Protein Kinase A and Protein Kinase C signaling

“…*Po0.05, **Po0.01, ***Po0.001 modulating neuronal growth, remodeling and survival. 21,49,50 In light of our previous findings, 11 sPIF downregulates microRNA let-7 expression through PI3K/Akt signaling, also in a TLR4-dependent manner reducing neuronal death. Meanwhile, decreased let-7 levels lead to increased expression of IL10, a direct target of let-7-mediated inhibition 55,56 and a potent anti-inflammatory cytokine in neuroprotection.…”

“…20 In the case of brain injury, activation of the PKA/ PKC signaling pathways imparts neuroprotection by increasing expression of anti-apoptotic and neurotrophic molecules while reducing pro-apoptotic molecules in neurons. [21][22][23] Not surprisingly, PKA/PKC pathways have been recognized as potent targets for neuroprotective strategies.…”

“…21,39 Growthassociated protein 43 (GAP-43) is a well-established marker of neuronal plasticity with increased expression during neuronal recovery. 40,41 Importantly, phosphorylation at Ser41 regulates GAP-43 interaction with the cytoskeleton, promoting neurite outgrowth 42 and dephosphorylation results in cytoskeleton destruction and growth cone collapse.…”

“…45,46 Phosphorylation of CREBSer133 leads to recruitment of CREB-binding protein (CBP) at the promoter regions of cAMP-responsive genes including Gap43, Bcl2 and Bdnf, 40,47,48 which impart neuroprotection. 21,49,50 In summary, phosphorylation of all three proteins (BAD, GAP-43 and CREB) results in broad neuroprotective effects and represents a target for neuroprotective strategies. Thus, we tested the three PKA/PKC substrates in our perinatal brain injury model.…”

Temporal and Spatial Changes in the Pattern of Iba1 and CD68 Staining in the Rat Brain Following Severe Traumatic Brain Injury

“…Along with rod-shapedIba1 + cells, phagocytic (CD68 + ) and amoeboid Iba1 + cells increased in the cortex at later time points. The increase of Iba1 + cells seen within the cortex could be associated with the recently reported neuroprotective synaptic stripping; further analysis of the functional consequences of the observed neuroinflammation is needed [13] [37]. Perez-Polo et al [15] showed that at 6 hours after mild TBI one of the structures most affected by the pro-inflammatory cytokine IL-1β was the ipsilateral hippocampus.…”