Neurons and neuronal activity control gene expression in astrocytes to regulate their development and metabolism

Philip Hasel, Owen Dando, Zoeb Jiwaji, Paul Baxter, Alison C. Todd, Samuel Heron, Nóra M. Márkus, Jamie McQueen, David W. Hampton, Megan Torvell, Sachin S. Tiwari, Sean McKay, Abel Eraso-Pichot, Antonio Zorzano, Roser Masgrau, Elena Galea, Siddharthan Chandran, David J. A. Wyllie, T. Ian Simpson and Giles E. Hardingham ()
Additional contact information
Philip Hasel: Deanery of Biomedical Sciences, Edinburgh Medical School, University of Edinburgh
Owen Dando: Deanery of Biomedical Sciences, Edinburgh Medical School, University of Edinburgh
Zoeb Jiwaji: Deanery of Biomedical Sciences, Edinburgh Medical School, University of Edinburgh
Paul Baxter: Deanery of Biomedical Sciences, Edinburgh Medical School, University of Edinburgh
Alison C. Todd: Deanery of Biomedical Sciences, Edinburgh Medical School, University of Edinburgh
Samuel Heron: School of Informatics, University of Edinburgh
Nóra M. Márkus: Deanery of Biomedical Sciences, Edinburgh Medical School, University of Edinburgh
Jamie McQueen: Deanery of Biomedical Sciences, Edinburgh Medical School, University of Edinburgh
David W. Hampton: MRC Centre for Regenerative Medicine, University of Edinburgh
Megan Torvell: MRC Centre for Regenerative Medicine, University of Edinburgh
Sachin S. Tiwari: MRC Centre for Regenerative Medicine, University of Edinburgh
Sean McKay: Deanery of Biomedical Sciences, Edinburgh Medical School, University of Edinburgh
Abel Eraso-Pichot: Institut de Neurociències and Departament de Bioquímica i Biologia Molecular, Unitat de Bioquímica de Medicina, Edifici M, Universitat Autònoma de Barcelona
Antonio Zorzano: Institute for Research in Biomedicine
Roser Masgrau: Institut de Neurociències and Departament de Bioquímica i Biologia Molecular, Unitat de Bioquímica de Medicina, Edifici M, Universitat Autònoma de Barcelona
Elena Galea: Institut de Neurociències and Departament de Bioquímica i Biologia Molecular, Unitat de Bioquímica de Medicina, Edifici M, Universitat Autònoma de Barcelona
Siddharthan Chandran: MRC Centre for Regenerative Medicine, University of Edinburgh
David J. A. Wyllie: Deanery of Biomedical Sciences, Edinburgh Medical School, University of Edinburgh
T. Ian Simpson: School of Informatics, University of Edinburgh
Giles E. Hardingham: Deanery of Biomedical Sciences, Edinburgh Medical School, University of Edinburgh

Nature Communications, 2017, vol. 8, issue 1, 1-18

Abstract: Abstract The influence that neurons exert on astrocytic function is poorly understood. To investigate this, we first developed a system combining cortical neurons and astrocytes from closely related species, followed by RNA-seq and in silico species separation. This approach uncovers a wide programme of neuron-induced astrocytic gene expression, involving Notch signalling, which drives and maintains astrocytic maturity and neurotransmitter uptake function, is conserved in human development, and is disrupted by neurodegeneration. Separately, hundreds of astrocytic genes are acutely regulated by synaptic activity via mechanisms involving cAMP/PKA-dependent CREB activation. This includes the coordinated activity-dependent upregulation of major astrocytic components of the astrocyte–neuron lactate shuttle, leading to a CREB-dependent increase in astrocytic glucose metabolism and elevated lactate export. Moreover, the groups of astrocytic genes induced by neurons or neuronal activity both show age-dependent decline in humans. Thus, neurons and neuronal activity regulate the astrocytic transcriptome with the potential to shape astrocyte–neuron metabolic cooperation.

Date: 2017
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DOI: 10.1038/ncomms15132

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