From neurons to the neuro-glio-vascular unit: Seizures and brain homeostasis in networks.

While seizures are undoubtedly neuronal events, an ensemble of auxiliary brain cells profoundly shapes synaptic transmission in health and disease conditions. Endothelial-astrocyte-pericyte assemblies at the blood-brain barrier (BBB) and neuroglia within the neuro-glio-vascular unit (NGVU) finely tune brain parenchymal homeostasis, safeguarding the ionic and molecular compositions of the interstitial fluid. BBB permeability with neuroinflammation and the resulting loss of brain homeostatic control are unifying mechanisms sustaining aberrant neuronal discharges, with temporal specificities linked to acute (head trauma, stroke, infections) and pre-existent (genetic) or chronic ( dysplasia, tumors, neurodegenerative disorders) pathological conditions. Within this research template, one hypothesis is that the topography of BBB damage and neuroinflammation could associate with symptoms, e.g., limbic structures for seizures or pre-frontal for psychiatric episodes. Another uncharted matter is whether seizure activity, without tissue lesions or sclerosis, is sufficient to promote stable cellular-level maladaptations in networks. Contingent to localization and duration, BBB damage and inflammation forecast pathological trajectories, and the concept of an epileptic NGVU could enable time-sensitive biomarkers to predict disease progression. The coherence between electrographic, imaging and molecular NGVU biomarkers could be established from the epileptogenic to the propagating zones. This paradigm shift could lead to new diagnostic and therapeutic modalities germane to specific epilepsies or when seizure activity represents a comorbidity.

Nrf2-dependent persistent oxidative stress results in stress-induced vulnerability to depression.

Stressful life events produce a state of vulnerability to depression in some individuals. The mechanisms that contribute to vulnerability to depression remain poorly understood. A rat model of intense stress (social defeat (SD), first hit) produced vulnerability to depression in 40% of animals. Only vulnerable animals developed a depression-like phenotype after a second stressful hit (chronic mild stress). We found that this vulnerability to depression resulted from a persistent state of oxidative stress, which was reversed by treatment with antioxidants. This persistent state of oxidative stress was due to low brain-derived neurotrophic factor (BDNF) levels, which characterized the vulnerable animals. We found that BDNF constitutively controlled the nuclear translocation of the master redox-sensitive transcription factor Nrf2, which activates antioxidant defenses. Low BDNF levels in vulnerable animals prevented Nrf2 translocation and consequently prevented the activation of detoxifying/antioxidant enzymes, ultimately resulting in the generation of sustained oxidative stress. Activating Nrf2 translocation restored redox homeostasis and reversed vulnerability to depression. This mechanism was confirmed in Nrf2-null mice. The mice displayed high levels of oxidative stress and were inherently vulnerable to depression, but this phenotype was reversed by treatment with antioxidants. Our data reveal a novel role for BDNF in controlling redox homeostasis and provide a mechanistic explanation for post-stress vulnerability to depression while suggesting ways to reverse it. Because numerous enzymatic reactions produce reactive oxygen species that must then be cleared, the finding that BDNF controls endogenous redox homeostasis opens new avenues for investigation.

Nrf2-dependent persistent oxidative stress results in stress-induced vulnerability to depression.

This corrects the article DOI: 10.1038/mp.2016.144.