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Nat Commun. 2017 May 2;8:15132. doi: 10.1038/ncomms15132.

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

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Deanery of Biomedical Sciences, Edinburgh Medical School, University of Edinburgh, Edinburgh EH8 9XD, UK.
MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4SB, UK.
Centre for Brain Development and Repair, Institute for Stem Cell Biology and Regenerative Medicine, National Centre for Biological Sciences, Bangalore 560065, India.
School of Informatics, University of Edinburgh, Edinburgh EH8 9AB, UK.
Institut de Neurociències and Departament de Bioquímica i Biologia Molecular, Unitat de Bioquímica de Medicina, Edifici M, Universitat Autònoma de Barcelona, Bellaterra, Barcelona 08193, Spain.
Institute for Research in Biomedicine, Barcelona 08028, Spain.
Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona 08028, Spain.
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid 28029, Spain.
Institució Catalana De Recerca I Estudis Avançats (ICREA), Passeig Lluís Companys 23, Barcelona, Catalonia, 08010, Spain.
10UK Dementia Research Institute at The University of Edinburgh, Edinburgh Medical School, 47 Little France Crescent, Edinburgh EH16 4TJ, , UK.


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.

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