RESUMO
Intrinsic antioxidant defenses are important for neuronal longevity. We found that in rat neurons, synaptic activity, acting via NMDA receptor (NMDAR) signaling, boosted antioxidant defenses by making changes to the thioredoxin-peroxiredoxin (Prx) system. Synaptic activity enhanced thioredoxin activity, facilitated the reduction of overoxidized Prxs and promoted resistance to oxidative stress. Resistance was mediated by coordinated transcriptional changes; synaptic NMDAR activity inactivated a previously unknown Forkhead box O target gene, the thioredoxin inhibitor Txnip. Conversely, NMDAR blockade upregulated Txnip in vivo and in vitro, where it bound thioredoxin and promoted vulnerability to oxidative damage. Synaptic activity also upregulated the Prx reactivating genes Sesn2 (sestrin 2) and Srxn1 (sulfiredoxin), via C/EBPbeta and AP-1, respectively. Mimicking these expression changes was sufficient to strengthen antioxidant defenses. Trans-synaptic stimulation of synaptic NMDARs was crucial for boosting antioxidant defenses; chronic bath activation of all (synaptic and extrasynaptic) NMDARs induced no antioxidative effects. Thus, synaptic NMDAR activity may influence the progression of pathological processes associated with oxidative damage.
Assuntos
Antioxidantes/metabolismo , Estresse Oxidativo/fisiologia , Peroxirredoxinas/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Tiorredoxinas/metabolismo , Animais , Proteínas de Transporte/metabolismo , Células Cultivadas , Córtex Cerebral/citologia , Córtex Cerebral/metabolismo , Regulação da Expressão Gênica/fisiologia , Camundongos , Neurônios/metabolismo , Proteínas Nucleares , Oxirredutases atuantes sobre Doadores de Grupo Enxofre/metabolismo , Peroxidases , Proteínas/metabolismo , Ratos , Transdução de Sinais/fisiologia , Sinapses/metabolismo , Transmissão Sináptica/fisiologia , Transcrição Gênica/fisiologiaRESUMO
Myelin, the insulating layers of membrane wrapped around axons by oligodendrocytes, is essential for normal impulse conduction. It forms during late stages of fetal development but continues into early adult life. Myelination correlates with cognitive development and can be regulated by impulse activity through unknown molecular mechanisms. Astrocytes do not form myelin, but these nonneuronal cells can promote myelination in ways that are not understood. Here, we identify a link between myelination, astrocytes, and electrical impulse activity in axons that is mediated by the cytokine leukemia inhibitory factor (LIF). These findings show that LIF is released by astrocytes in response to ATP liberated from axons firing action potentials, and LIF promotes myelination by mature oligodendrocytes. This activity-dependent mechanism promoting myelination could regulate myelination according to functional activity or environmental experience and may offer new approaches to treating demyelinating diseases.
Assuntos
Astrócitos/efeitos da radiação , Comunicação Celular/fisiologia , Estimulação Elétrica/métodos , Proteínas da Mielina/metabolismo , Oligodendroglia/fisiologia , Potenciais de Ação/fisiologia , Potenciais de Ação/efeitos da radiação , Adenosina/farmacologia , Trifosfato de Adenosina/análogos & derivados , Trifosfato de Adenosina/metabolismo , Trifosfato de Adenosina/farmacologia , Adenosina-5'-(N-etilcarboxamida)/farmacologia , Anestésicos Locais/farmacologia , Animais , Anticorpos/farmacologia , Astrócitos/fisiologia , Axônios/efeitos dos fármacos , Axônios/metabolismo , Axônios/efeitos da radiação , Compostos Azo , Western Blotting/métodos , Comunicação Celular/efeitos dos fármacos , Comunicação Celular/efeitos da radiação , Contagem de Células/métodos , Células Cultivadas , Córtex Cerebral/citologia , Técnicas de Cocultura/métodos , Proteínas de Ligação a DNA/metabolismo , Relação Dose-Resposta a Droga , Proteínas de Drosophila/metabolismo , Interações Medicamentosas , Embrião de Mamíferos , Ensaio de Imunoadsorção Enzimática/métodos , Gânglios Espinais/citologia , Expressão Gênica/efeitos dos fármacos , Imuno-Histoquímica/métodos , Interleucina-6/imunologia , Interleucina-6/metabolismo , Fator Inibidor de Leucemia , Camundongos , Modelos Biológicos , Proteína Básica da Mielina/metabolismo , Glicoproteína Associada a Mielina/metabolismo , Glicoproteína Mielina-Oligodendrócito , Naftalenos , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Antígenos O/metabolismo , RNA Mensageiro/biossíntese , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Células-Tronco , Tetrodotoxina/farmacologia , Tionucleotídeos/farmacologiaRESUMO
Alzheimer's disease and other neurodegenerative disorders of aging are characterized by clinical and pathological features that are relatively specific to humans. To obtain greater insight into how brain aging has evolved, we compared age-related gene expression changes in the cortex of humans, rhesus macaques, and mice on a genome-wide scale. A small subset of gene expression changes are conserved in all three species, including robust age-dependent upregulation of the neuroprotective gene apolipoprotein D (APOD) and downregulation of the synaptic cAMP signaling gene calcium/calmodulin-dependent protein kinase IV (CAMK4). However, analysis of gene ontology and cell type localization shows that humans and rhesus macaques have diverged from mice due to a dramatic increase in age-dependent repression of neuronal genes. Many of these age-regulated neuronal genes are associated with synaptic function. Notably, genes associated with GABA-ergic inhibitory function are robustly age-downregulated in humans but not in mice at the level of both mRNA and protein. Gene downregulation was not associated with overall neuronal or synaptic loss. Thus, repression of neuronal gene expression is a prominent and recently evolved feature of brain aging in humans and rhesus macaques that may alter neural networks and contribute to age-related cognitive changes.