title: Conditions and constraints for astrocyte calcium signaling in the hippocampal mossy fiber pathway.
abstract: The spatiotemporal activities of astrocyte Ca²⁺ signaling in mature neuronal circuits remain unclear. We used genetically encoded Ca²⁺ and glutamate indicators as well as pharmacogenetic and electrical control of neurotransmitter release to explore astrocyte activity in the hippocampal mossy fiber pathway. Our data revealed numerous localized, spontaneous Ca²⁺ signals in astrocyte branches and territories, but these were not driven by neuronal activity or glutamate. Moreover, evoked astrocyte Ca²⁺ signaling changed linearly with the number of mossy fiber action potentials. Under these settings, astrocyte responses were global, suppressed by neurotransmitter clearance, and mediated by glutamate and GABA. Thus, astrocyte engagement in the fully developed mossy fiber pathway was slow and territorial, contrary to that frequently proposed for astrocytes within microcircuits. We show that astrocyte Ca²⁺ signaling functionally segregates large volumes of neuropil and that these transients are not suited for responding to, or regulating, single synapses in the mossy fiber pathway.
authors.affiliation: Department of Physiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095-1751, USA.
authors.forename: Martin D
authors.initials: MD
authors.lastname: Haustein
authors.affiliation: Department of Physiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095-1751, USA.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kracun
authors.affiliation: Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095-1751, USA.
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Lu
authors.affiliation: National Center for Microscopy and Imaging Research and Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Shih
authors.affiliation: Department of Physiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095-1751, USA.
authors.forename: Olan
authors.initials: O
authors.lastname: Jackson-Weaver
authors.affiliation: Department of Physiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095-1751, USA.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Tong
authors.affiliation: Department of Physiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095-1751, USA.
authors.forename: Ji
authors.initials: J
authors.lastname: Xu
authors.affiliation: Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095-1751, USA.
authors.forename: X William
authors.initials: XW
authors.lastname: Yang
authors.affiliation: Department of Physiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095-1751, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: O'Dell
authors.affiliation: Janelia Farm Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Marvin
authors.affiliation: National Center for Microscopy and Imaging Research and Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Ellisman
authors.affiliation: National Center for Microscopy and Imaging Research and Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Bushong
authors.affiliation: Janelia Farm Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA.
authors.forename: Loren L
authors.initials: LL
authors.lastname: Looger
authors.affiliation: Department of Physiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095-1751, USA; Department of Neurobiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095-1751, USA. Electronic address: bkhakh@mednet.ucla.edu.
authors.forename: Baljit S
authors.initials: BS
authors.lastname: Khakh
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D005260:Female; D018682:GABA Agents / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019599:Mossy Fibers, Hippocampal / Q000187:drug effects / Q000502:physiology*; D018080:Receptors, GABA-B / Q000235:genetics; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics; D026941:Sodium Channel Blockers / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism / Q000494:pharmacology
chemical_list: D018683:Excitatory Amino Acid Agents; D018682:GABA Agents; D018080:Receptors, GABA-B; D018094:Receptors, Metabotropic Glutamate; D026941:Sodium Channel Blockers; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid
references.citation: J Neurosci. 2012 Feb 29;32(9):3131-41
references.pmid: 22378886
references.citation: Neuroscientist. 2011 Oct;17(5):513-23
references.pmid: 21536839
references.citation: Neuron. 2008 Sep 25;59(6):932-46
references.pmid: 18817732
references.citation: Nat Methods. 2013 Feb;10(2):162-70
references.pmid: 23314171
references.citation: Nat Neurosci. 2010 Jun;13(6):759-66
references.pmid: 20495558
references.citation: Trends Neurosci. 2005 Jun;28(6):297-303
references.pmid: 15927685
references.citation: Front Pharmacol. 2012 Jul 13;3:139
references.pmid: 22811669
references.citation: J Neurosci. 2008 Jun 25;28(26):6659-63
references.pmid: 18579739
references.citation: Nat Neurosci. 2006 Jun;9(6):816-23
references.pmid: 16699507
references.citation: Neuron. 2012 Oct 4;76(1):51-69
references.pmid: 23040806
references.citation: J Neurosci. 2011 Jun 22;31(25):9353-8
references.pmid: 21697385
references.citation: J Gen Physiol. 2013 May;141(5):633-47
references.pmid: 23589582
references.citation: Neuroscientist. 2013 Jun;19(3):274-91
references.pmid: 23264008
references.citation: Nat Neurosci. 2011 Dec 11;15(1):70-80
references.pmid: 22158513
references.citation: Science. 2013 Jan 11;339(6116):197-200
references.pmid: 23307741
references.citation: Prog Brain Res. 2012;196:79-94
references.pmid: 22341322
references.citation: J Struct Biol. 1996 Jan-Feb;116(1):71-6
references.pmid: 8742726
references.citation: Neuron. 2009 Nov 12;64(3):391-403
references.pmid: 19914187
references.citation: Front Neural Circuits. 2013 Jan 09;6:112
references.pmid: 23316138
references.citation: Science. 2010 Mar 5;327(5970):1250-4
references.pmid: 20203048
references.citation: J Neurosci. 2008 May 7;28(19):4967-73
references.pmid: 18463250
references.citation: Proc Natl Acad Sci U S A. 2007 Feb 6;104(6):1995-2000
references.pmid: 17259307
references.citation: Curr Biol. 2003 May 13;13(10):872-6
references.pmid: 12747838
references.citation: Neuron. 1996 Mar;16(3):675-86
references.pmid: 8785064
references.citation: Nat Neurosci. 1998 Dec;1(8):683-92
references.pmid: 10196584
references.citation: Nat Methods. 2009 Dec;6(12):875-81
references.pmid: 19898485
references.citation: Nature. 2010 Nov 11;468(7321):232-43
references.pmid: 21068832
references.citation: Neuron. 2007 May 24;54(4):611-26
references.pmid: 17521573
references.citation: Proc R Soc Lond B Biol Sci. 1967 Jun 6;168(1010):1-21
references.pmid: 4382871
references.citation: Nat Methods. 2008 Jan;5(1):87-93
references.pmid: 18084300
references.citation: Nature. 2013 Jul 18;499(7458):295-300
references.pmid: 23868258
references.citation: J Neurosci. 2013 Jan 30;33(5):1755-6
references.pmid: 23365214
references.citation: J Neurosci. 2007 Jun 20;27(25):6607-19
references.pmid: 17581948
references.citation: J Neurosci. 2013 Jun 12;33(24):10143-53
references.pmid: 23761909
references.citation: Front Cell Neurosci. 2013 Oct 29;7:193
references.pmid: 24194698
references.citation: Cell Tissue Res. 2006 Nov;326(2):221-37
references.pmid: 16932936
references.citation: Mol Aspects Med. 2013 Apr-Jun;34(2-3):108-20
references.pmid: 23506861
references.citation: J Neurosci. 2004 May 12;24(19):4551-9
references.pmid: 15140926
references.citation: J Neurosci. 2013 Jan 9;33(2):507-22
references.pmid: 23303931
references.citation: Epilepsia. 2002;43 Suppl 5:196-202
references.pmid: 12121321
references.citation: Nat Neurosci. 2011 Sep 11;14(10):1276-84
references.pmid: 21909085
references.citation: J Neurosci. 2007 Sep 26;27(39):10434-44
references.pmid: 17898215
references.citation: Cell. 2011 Sep 2;146(5):785-98
references.pmid: 21855979
references.citation: Circ Res. 2005 Jun 24;96(12):1274-81
references.pmid: 15933266