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1.
Nat Neurosci ; 2024 Sep 09.
Artículo en Inglés | MEDLINE | ID: mdl-39251890

RESUMEN

Brain function requires a constant supply of glucose. However, the brain has no known energy stores, except for glycogen granules in astrocytes. In the present study, we report that continuous oligodendroglial lipid metabolism provides an energy reserve in white matter tracts. In the isolated optic nerve from young adult mice of both sexes, oligodendrocytes survive glucose deprivation better than astrocytes. Under low glucose, both axonal ATP levels and action potentials become dependent on fatty acid ß-oxidation. Importantly, ongoing oligodendroglial lipid degradation feeds rapidly into white matter energy metabolism. Although not supporting high-frequency spiking, fatty acid ß-oxidation in mitochondria and oligodendroglial peroxisomes protects axons from conduction blocks when glucose is limiting. Disruption of the glucose transporter GLUT1 expression in oligodendrocytes of adult mice perturbs myelin homeostasis in vivo and causes gradual demyelination without behavioral signs. This further suggests that the imbalance of myelin synthesis and degradation can underlie myelin thinning in aging and disease.

3.
Nat Neurosci ; 27(3): 433-448, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38267524

RESUMEN

The integrity of myelinated axons relies on homeostatic support from oligodendrocytes (OLs). To determine how OLs detect axonal spiking and how rapid axon-OL metabolic coupling is regulated in the white matter, we studied activity-dependent calcium (Ca2+) and metabolite fluxes in the mouse optic nerve. We show that fast axonal spiking triggers Ca2+ signaling and glycolysis in OLs. OLs detect axonal activity through increases in extracellular potassium (K+) concentrations and activation of Kir4.1 channels, thereby regulating metabolite supply to axons. Both pharmacological inhibition and OL-specific inactivation of Kir4.1 reduce the activity-induced axonal lactate surge. Mice lacking oligodendroglial Kir4.1 exhibit lower resting lactate levels and altered glucose metabolism in axons. These early deficits in axonal energy metabolism are associated with late-onset axonopathy. Our findings reveal that OLs detect fast axonal spiking through K+ signaling, making acute metabolic coupling possible and adjusting the axon-OL metabolic unit to promote axonal health.


Asunto(s)
Axones , Sustancia Blanca , Ratones , Animales , Axones/fisiología , Oligodendroglía/metabolismo , Sustancia Blanca/metabolismo , Homeostasis , Lactatos/metabolismo
4.
Cell Rep ; 38(10): 110484, 2022 03 08.
Artículo en Inglés | MEDLINE | ID: mdl-35263595

RESUMEN

The mechanisms by which astrocytes modulate neural homeostasis, synaptic plasticity, and memory are still poorly explored. Astrocytes form large intercellular networks by gap junction coupling, mainly composed of two gap junction channel proteins, connexin 30 (Cx30) and connexin 43 (Cx43). To circumvent developmental perturbations and to test whether astrocytic gap junction coupling is required for hippocampal neural circuit function and behavior, we generate and study inducible, astrocyte-specific Cx30 and Cx43 double knockouts. Surprisingly, disrupting astrocytic coupling in adult mice results in broad activation of astrocytes and microglia, without obvious signs of pathology. We show that hippocampal CA1 neuron excitability, excitatory synaptic transmission, and long-term potentiation are significantly affected. Moreover, behavioral inspection reveals deficits in sensorimotor performance and a complete lack of spatial learning and memory. Together, our findings establish that astrocytic connexins and an intact astroglial network in the adult brain are vital for neural homeostasis, plasticity, and spatial cognition.


Asunto(s)
Astrocitos , Conexina 43 , Animales , Astrocitos/metabolismo , Conexina 30/metabolismo , Conexina 43/metabolismo , Conexinas/metabolismo , Uniones Comunicantes/metabolismo , Ratones , Plasticidad Neuronal/fisiología , Aprendizaje Espacial
5.
Nat Metab ; 2(2): 179-191, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-32694692

RESUMEN

It has been suggested that, in states of arousal, release of noradrenaline and ß-adrenergic signalling affect long-term memory formation by stimulating astrocytic lactate production from glycogen. However, the temporal relationship between cortical activity and cellular lactate fluctuations upon changes in arousal remains to be fully established. Also, the role of ß-adrenergic signalling and brain glycogen metabolism on neural lactate dynamics in vivo is still unknown. Here, we show that an arousal-induced increase in cortical activity triggers lactate release into the extracellular space, and this correlates with a fast and prominent lactate dip in astrocytes. The immediate drop in astrocytic lactate concentration and the parallel increase in extracellular lactate levels underline an activity-dependent lactate release from astrocytes. Moreover, when ß-adrenergic signalling is blocked or the brain is depleted of glycogen, the arousal-evoked cellular lactate surges are significantly reduced. We provide in vivo evidence that cortical activation upon arousal triggers lactate release from astrocytes, a rise in intracellular lactate levels mediated by ß-adrenergic signalling and the mobilization of lactate from glycogen stores.


Asunto(s)
Nivel de Alerta , Astrocitos/metabolismo , Corteza Cerebral/fisiología , Ácido Láctico/metabolismo , Animales , Corteza Cerebral/metabolismo , Electroencefalografía , Ratones , Receptores Adrenérgicos beta/metabolismo , Transducción de Señal
6.
Front Cell Neurosci ; 12: 377, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30405358

RESUMEN

Myelination of axons by oligodendrocytes is a key feature of the remarkably fast operating CNS. Oligodendrocytes not only tune axonal conduction speed but are also suggested to maintain long-term axonal integrity by providing metabolic support to the axons they ensheath. However, how myelinating oligodendrocytes impact axonal energy homeostasis remains poorly understood and difficult to investigate. Here, we provide a method of how to study electrically active myelinated axons expressing genetically encoded sensors by combining electrophysiology and two-photon imaging of acutely isolated optic nerves. We show that intravitreal adeno-associated viral (AAV) vector delivery is an efficient tool to achieve functional sensor expression in optic nerve axons, which is demonstrated by measuring axonal ATP dynamics following AAV-mediated sensor expression. This novel approach allows for fast expression of any optical sensor of interest to be studied in optic nerve axons without the need to go through the laborious process of producing new transgenic mouse lines. Viral-mediated biosensor expression in myelinated axons and the subsequent combination of nerve recordings and sensor imaging outlines a powerful method to investigate oligodendroglial support functions and to further interrogate cellular mechanisms governing axonal energy homeostasis under physiological and pathological conditions.

7.
Cereb Cortex ; 28(1): 184-198, 2018 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-28968832

RESUMEN

Localized, heterogeneous calcium transients occur throughout astrocytes, but the characteristics and long-term stability of these signals, particularly in response to sensory stimulation, remain unknown. Here, we used a genetically encoded calcium indicator and an activity-based image analysis scheme to monitor astrocyte calcium activity in vivo. We found that different subcellular compartments (processes, somata, and endfeet) displayed distinct signaling characteristics. Closer examination of individual signals showed that sensory stimulation elevated the number of specific types of calcium peaks within astrocyte processes and somata, in a cortical layer-dependent manner, and that the signals became more synchronous upon sensory stimulation. Although mice genetically lacking astrocytic IP3R-dependent calcium signaling (Ip3r2-/-) had fewer signal peaks, the response to sensory stimulation was sustained, suggesting other calcium pathways are also involved. Long-term imaging of astrocyte populations revealed that all compartments reliably responded to stimulation over several months, but that the location of the response within processes may vary. These previously unknown characteristics of subcellular astrocyte calcium signals provide new insights into how astrocytes may encode local neuronal circuit activity.


Asunto(s)
Astrocitos/metabolismo , Señalización del Calcio/fisiología , Calcio/metabolismo , Percepción/fisiología , Corteza Somatosensorial/metabolismo , Animales , Astrocitos/citología , Femenino , Miembro Posterior/fisiología , Inmunohistoquímica , Receptores de Inositol 1,4,5-Trifosfato/deficiencia , Receptores de Inositol 1,4,5-Trifosfato/genética , Ratones Endogámicos C57BL , Ratones Noqueados , Imagen Óptica , Optogenética , Estimulación Física , Corteza Somatosensorial/citología , Fracciones Subcelulares/metabolismo , Vibrisas/fisiología
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