Astrocyte NMDA receptors' activity sustains neuronal survival through a Cdk5–Nrf2 pathway

Abstract

Neurotransmission unavoidably increases mitochondrial reactive oxygen species. However, the intrinsic antioxidant defense of neurons is weak and hence the mechanism whereby these cells are physiologically protected against oxidative damage is unknown. Here we found that the antioxidant defense of neurons is repressed owing to the continuous protein destabilization of the master antioxidant transcriptional activator, nuclear factor-erythroid 2-related factor-2 (Nrf2). By contrast, Nrf2 is highly stable in neighbor astrocytes explaining their robust antioxidant defense and resistance against oxidative stress. We also show that subtle and persistent stimulation of N-methyl-D-aspartate receptors (NMDAR) in astrocytes, through a mechanism not requiring extracellular Ca 2+ influx, upregulates a signal transduction pathway involving phospholipase C-mediated endoplasmic reticulum release of Ca 2+ and protein kinase Cδ activation. Active protein kinase Cδ promotes, by phosphorylation, the stabilization of p35, a cyclin-dependent kinase-5 (Cdk5) cofactor. Active p35/Cdk5 complex in the cytosol phosphorylates Nrf2 at Thr 395 , Ser 433 and Thr 439 that is sufficient to promote Nrf2 translocation to the nucleus and induce the expression of antioxidant genes. Furthermore, this Cdk5-Nrf2 transduction pathway boosts glutathione metabolism in astrocytes efficiently protecting closely spaced neurons against oxidative damage. Thus, intercellular communication through NMDAR couples neurotransmission with neuronal survival.

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

“…Under normal unstressed conditions, Nrf2 is anchored to Keap1 and rapidly degraded (Itoh et al, 2003; McMahon, Itoh, Yamamoto, & Hayes, 2003). This process seems to be much more powerful in neurons than in astrocytes (Jimenez‐Blasco, Santofimia‐Castano, Gonzalez, Almeida, & Bolanos, 2015). Oxidative stress or exposure to electrophilic agents that react with Keap1 slow down Nrf2 degradation and lead to its nuclear accumulation.…”

Complex I assembly into supercomplexes determines differential mitochondrial ROS production in neurons and astrocytes

“…Thus, astrocytes are equipped to protect themselves when exposed to excess reactive oxygen species (ROS) (12) and reactive nitrogen species (13,14). Moreover, astrocytes also provide nearby neurons with protective antioxidant precursors through a cell-signaling mechanism involving glutamate receptor activation by neurotransmission (11,15,16). The tight coupling between astrocytes and neurons therefore helps in energy and redox metabolism during normal brain function.…”

“…Astrocytes provide crucial metabolic and structural support (3,4) and are key players in neurotransmission (5-7) and behavior (8). The status of many major redox couples in the brain is also regulated by astrocytes (9), through their high content of antioxidant compounds and enzymes (10) and by the constitutive stabilization of the master antioxidant transcriptional activator, nuclear factor erythroid 2-related factor 2 (Nrf2) (11). Thus, astrocytes are equipped to protect themselves when exposed to excess reactive oxygen species (ROS) (12) and reactive nitrogen species (13,14).…”

NMDA Receptors in Astroglia: Chronology, Controversies, and Contradictions from a Complex Molecule

“…In fact, this has been confirmed by different works, but with some differences in comparison with synaptic NMDAR signaling described above. Activation of PLC/PKC/ p35/Cdk5/Nrf2, a prosurvival pathway, and CAPON nuclear translocation were described in cultured astrocytes in response to NMDAR [114,126]. On the other hand, MK-801 treatment of cultured astrocytes upregulated glycogen phosphorylase and regulated the expression of growth and metabolic genes [134].…”

“…The same year, Jimenez-Blasco et al [126] reported that in cultured rat cortical astrocytes they observed iCa…”