Sustained neuronal activity drives metabolic changes in astrocytes

1. Centre for Integrative Physiology, Edinburgh Medical School: Biomedical Sciences, University of Edinburgh
2. Centre for Regenerative Medicine, University of Edinburgh

The brain is metabolically the most active organ in the body, and disruptions in CNS metabolism have been implicated in several neurodegenerative diseases (1). The astrocyte-neuron lactate shuttle (ANLS) hypothesis proposes that astrocytes have a key role in CNS metabolic homeostasis, converting glucose to lactate as an energy substrate to fuel neuronal metabolism (2). Lactate provision is coupled to glutamatergic transmission, increasing metabolic supply to meet acute changes in neuronal demand (3). However, the consequences of sustained periods of altered neuronal activity on astrocyte metabolic capacity are unknown.

To investigate this, we cocultured primary mouse or human pluripotent stem cell-derived astrocytes cocultured with primary cortical neurons. Neuronal activity was altered for 24hrs with bicuculline (Bic – high activity) or tetrodotoxin (TTX – low activity). Astrocyte metabolic flux was determined using fluorescence-resonance energy transfer (FRET) optical biosensors for glucose or lactate, and measuring the rate of change in metabolite concentration following inhibition of glucose uptake or lactate export.

We found that astrocytes exposed to 24hrs of high neuronal activity (Bic) vs low-activity (TTX) have increased rates of glucose utilisation and lactate production, with metabolic changes persisting over 6hrs even after transfer from high to low-activity condition. To investigate the mechanism responsible for these changes in metabolic flux, we carried out transcriptomic analysis and found activity-dependent upregulation of major components of the astrocyte–neuron lactate shuttle pathway. Finally we determined a key role for the cAMP response-element binding protein (CREB) transcription factor pathway in driving these activity-dependent changes in astrocyte metabolism. Constitutively-active CREB was sufficient to increase astrocyte metabolism in low-activity conditions and inhibition of CREB activation reversed activity-induced effects.

Therefore, these data point towards a novel pathway by which active neurons are able to tune astrocyte function to regulate CNS metabolic homeostasis in rodents and humans, and may imply consequences for CNS metabolism when neuronal activity is disrupted during disease or neurodegeneration.  (

References

1. Cai, H. et al. Metabolic Dysfunction in Alzheimers Disease and Related Neurodegenerative Disorders. Curr. Alzheimer Res. 9, 5–17 (2012).
2. Weber, B. & Barros, L. F. The Astrocyte: Powerhouse and Recycling Center. Cold Spring Harb. Perspect. Biol. 1–16 (2015).
3. Pellerin, L. & Magistretti, P. J. Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. Proc. Natl. Acad. Sci. U. S. A. 91, 10625–9 (1994).

Funded by: The Wellcome Trust

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