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The human brain generally remains structurally and functionally sound for many decades, despite the post-mitotic and non-regenerative nature of neurons. This is testament to the brain's profound capacity for homeostasis: both neurons and glia have in-built mechanisms that enable them to mount adaptive or protective responses to potentially challenging situations, ensuring that cellular viability and functionality is maintained. The high and variable metabolic and mitochondrial activity of neurons places several demands on the brain, including the task of neutralizing the associated reactive oxygen species (ROS) produced, to limit the accumulation of oxidative damage. Astrocytes play a key role in providing antioxidant support to nearby neurons, and redox regulation of the astrocytic Nrf2 pathway represents a powerful homeostatic regulator of the large cohort of Nrf2-regulated antioxidant genes that they express. In contrast, the Nrf2 pathway is weak in neurons, robbing them of this particular homeostatic device. However, many neuronal antioxidant genes are controlled by synaptic activity, enabling activity-dependent increases in ROS production to be offset by enhanced antioxidant capacity of both glutathione and thioredoxin-peroxiredoxin systems. These distinct homeostatic mechanisms in neurons and astrocytes together combine to promote neuronal resistance to oxidative insults. Future investigations into signaling between distinct cell types within the neuro-glial unit are likely to uncover further mechanisms underlying redox homeostasis in the brain., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Pituitary adenylate cyclase-activating peptide (PACAP) is a neuroprotective peptide which exerts its effects mainly through the cAMP-protein kinase A (PKA) pathway. Here, we show that in cortical neurons, PACAP-induced PKA signaling exerts a major part of its neuroprotective effects indirectly, by triggering action potential (AP) firing. Treatment of cortical neurons with PACAP induces a rapid and sustained PKA-dependent increase in AP firing and associated intracellular Ca(2+) transients, which are essential for the anti-apoptotic actions of PACAP. Transient exposure to PACAP induces long-lasting neuroprotection in the face of apoptotic insults which is reliant on AP firing and the activation of cAMP response element (CRE) binding protein (CREB)-mediated gene expression. Although direct, activity-independent PKA signaling is sufficient to trigger phosphorylation on CREB's activating serine-133 site, this is insufficient for activation of CREB-mediated gene expression. Full activation is dependent on CREB-regulated transcription co-activator 1 (CRTC1), whose PACAP-induced nuclear import is dependent on firing activity-dependent calcineurin signaling. Over-expression of CRTC1 is sufficient to rescue PACAP-induced CRE-mediated gene expression in the face of activity-blockade, while dominant negative CRTC1 interferes with PACAP-induced, CREB-mediated neuroprotection. Thus, the enhancement of AP firing may play a significant role in the neuroprotective actions of PACAP and other adenylate cyclase-coupled ligands., (© 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.)

Microglia, brain-resident macrophages, require instruction from the CNS microenvironment to maintain their identity and morphology and regulate inflammatory responses, although what mediates this is unclear. Here, we show that neurons and astrocytes cooperate to promote microglial ramification, induce expression of microglial signature genes ordinarily lost in vitro and in age and disease in vivo , and repress infection- and injury-associated gene sets. The influence of neurons and astrocytes separately on microglia is weak, indicative of synergies between these cell types, which exert their effects via a mechanism involving transforming growth factor β2 (TGF-β2) signaling. Neurons and astrocytes also combine to provide immunomodulatory cues, repressing primed microglial responses to weak inflammatory stimuli (without affecting maximal responses) and consequently limiting the feedback effects of inflammation on the neurons and astrocytes themselves. These findings explain why microglia isolated ex vivo undergo de-differentiation and inflammatory deregulation and point to how disease- and age-associated changes may be counteracted. [Display omitted] • Neurons and astrocytes combine to promote the microglial homeostatic signature • This rescues changes that happen in microglia ex vivo and in disease • Mechanistically, this involves transforming growth factor beta 2 (TBGF-β2) signaling • Neurons and astrocytes also repress microglial inflammatory responses Baxter et al. show that the transformation of microglia from a healthy to disease-associated state can be suppressed by the combined actions of neurons and astrocytes via a mechanism involving TBGF-β2 signaling. They also repress exaggerated microglial responses to mild stimuli and limit the feedback signaling from activated microglia. [ABSTRACT FROM AUTHOR]