Astrocyte lipid metabolism is critical for synapse development and function in vivo.
The brain is considered to be autonomous in lipid synthesis with astrocytes producing lipids far more efficiently than neurons. Accordingly, it is generally assumed that astrocyte-derived lipids are taken up by neurons to support synapse formation and function. Initial confirmation of this assumption has been obtained in cell cultures, but whether astrocyte-derived lipids support synapses in vivo is not known. Here, we address this issue and determined the role of astrocyte lipid metabolism in hippocampal synapse formation and function in vivo. Hippocampal protein expression for the sterol regulatory element-binding protein (SREBP) and its target gene fatty acid synthase (Fasn) was found in astrocytes but not in neurons. Diminishing SREBP activity in astrocytes using mice in which the SREBP cleavage-activating protein (SCAP) was deleted from GFAP-expressing cells resulted in decreased cholesterol and phospholipid secretion by astrocytes. Interestingly, SCAP mutant mice showed more immature synapses, lower presynaptic protein SNAP-25 levels as well as reduced numbers of synaptic vesicles, indicating impaired development of the presynaptic terminal. Accordingly, hippocampal short-term and long-term synaptic plasticity were defective in mutant mice. These findings establish a critical role for astrocyte lipid metabolism in presynaptic terminal development and function in vivo. GLIA 2017;65:670-682.
Department of Molecular & Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University Amsterdam, De Boelelaan 1085, Amsterdam, 1081 HV, The Netherlands.
Anne-Lieke F
AF
van Deijk
Department of Molecular & Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University Amsterdam, De Boelelaan 1085, Amsterdam, 1081 HV, The Netherlands.
Nutabi
N
Camargo
Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University Amsterdam, De Boelelaan 1085, Amsterdam, 1081 HV, The Netherlands.
Jaap
J
Timmerman
Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University Amsterdam, De Boelelaan 1085, Amsterdam, 1081 HV, The Netherlands.
Tim
T
Heistek
Department of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, Yalelaan 1, 3584 CL Utrecht University, Utrecht, The Netherlands.
Jos F
JF
Brouwers
Department of Molecular & Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University Amsterdam, De Boelelaan 1085, Amsterdam, 1081 HV, The Netherlands.
Floriana
F
Mogavero
Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University Amsterdam, De Boelelaan 1085, Amsterdam, 1081 HV, The Netherlands.
Huibert D
HD
Mansvelder
Department of Molecular & Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University Amsterdam, De Boelelaan 1085, Amsterdam, 1081 HV, The Netherlands.
August B
AB
Smit
Department of Molecular & Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University Amsterdam, De Boelelaan 1085, Amsterdam, 1081 HV, The Netherlands.
Mark H G
0000-0002-3739-3755
MH
Verheijen
D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000648:ultrastructure; D002478:Cells, Cultured; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics* / Q000502:physiology; D054890:Fatty Acid Synthase, Type I / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism / Q000648:ultrastructure; D016622:Silver Staining; D013569:Synapses / Q000502:physiology* / Q000648:ultrastructure; D050825:Synaptosomal-Associated Protein 25 / Q000378:metabolism; D013574:Synaptosomes / Q000378:metabolism / Q000648:ultrastructure
D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C102196:SREBP cleavage-activating protein; D050825:Synaptosomal-Associated Protein 25; D049452:Green Fluorescent Proteins; D054890:Fatty Acid Synthase, Type I
FASN; SCAP; SNAP-25; SREBP; cholesterol; fatty acids; glia; hippocampus; interactions; plasticity