Abstract
Astrocytes tile the entire CNS. They are vital for neural circuit function, but have traditionally been viewed as simple, homogenous cells that serve the same essential supportive roles everywhere. Here, we summarize breakthroughs that instead indicate that astrocytes represent a population of complex and functionally diverse cells. Physiological diversity of astrocytes is apparent between different brain circuits and microcircuits, and individual astrocytes display diverse signaling in subcellular compartments. With respect to injury and disease, astrocytes undergo diverse phenotypic changes that may be protective or causative with regard to pathology in a context-dependent manner. These new insights herald the concept that astrocytes represent a diverse population of genetically tractable cells that mediate neural circuit–specific roles in health and disease.
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References
Allen, N.J. & Barres, B.A. Neuroscience: glia—more than just brain glue. Nature 457, 675–677 (2009).
Herculano-Houzel, S. The glia/neuron ratio: how it varies uniformly across brain structures and species and what that means for brain physiology and evolution. Glia 62, 1377–1391 (2014).
Insel, T.R., Landis, S.C. & Collins, F.S. Research priorities. The NIH BRAIN Initiative. Science 340, 687–688 (2013).
De Felipe, J. Cajal's Butterflies of the Soul: Science and Art (Oxford University Press, 2010).
Oberheim, N.A. et al. Uniquely hominid features of adult human astrocytes. J. Neurosci. 29, 3276–3287 (2009).
Kimelberg, H.K. Functions of mature mammalian astrocytes: a current view. Neuroscientist 16, 79–106 (2010).
Miller, R.H. & Raff, M.C. Fibrous and protoplasmic astrocytes are biochemically and developmentally distinct. J. Neurosci. 4, 585–592 (1984).
Mishima, T. & Hirase, H. In vivo intracellular recording suggests that gray matter astrocytes in mature cerebral cortex and hippocampus are electrophysiologically homogeneous. J. Neurosci. 30, 3093–3100 (2010).
Kuffler, S.W. Neuroglial cells: physiological properties and a potassium mediated effect of neuronal activity on the glial membrane potential. Proc. R. Soc. Lond. B Biol. Sci. 168, 1–21 (1967).
Orkand, R.K., Nicholls, J.G. & Kuffler, S.W. Effect of nerve impulses on the membrane potential of glial cells in the central nervous system of amphibia. J. Neurophysiol. 29, 788–806 (1966).
Zhang, Y. & Barres, B.A. Astrocyte heterogeneity: an underappreciated topic in neurobiology. Curr. Opin. Neurobiol. 20, 588–594 (2010).
Oberheim, N.A., Goldman, S.A. & Nedergaard, M. Heterogeneity of astrocytic form and function. Methods Mol. Biol. 814, 23–45 (2012).
Freeman, M.R. Specification and morphogenesis of astrocytes. Science 330, 774–778 (2010).
Freeman, M.R. & Rowitch, D.H. Evolving concepts of gliogenesis: a look way back and ahead to the next 25 years. Neuron 80, 613–623 (2013).
Eng, L.F., Gerstl, B. & Vanderhaeghen, J.J. A study of proteins in old multiple sclerosis plaques. Trans. Am. Soc. Neurochem. 1, 42 (1970).
Eng, L.F., Ghirnikar, R.S. & Lee, Y.L. Glial fibrillary acidic protein: GFAP—thirty-one years (1969–2000). Neurochem. Res. 25, 1439–1451 (2000).
Sofroniew, M.V. & Vinters, H.V. Astrocytes: biology and pathology. Acta Neuropathol. 119, 7–35 (2010).
Middeldorp, J. & Hol, E.M. GFAP in health and disease. Prog. Neurobiol. 93, 421–443 (2011).
Bush, T.G. et al. Fulminant jejuno-ileitis following ablation of enteric glia in adult transgenic mice. Cell 93, 189–201 (1998).
Garcia, A.D., Doan, N.B., Imura, T., Bush, T.G. & Sofroniew, M.V. GFAP-expressing progenitors are the principal source of constitutive neurogenesis in adult mouse forebrain. Nat. Neurosci. 7, 1233–1241 (2004).
Kriegstein, A. & Alvarez-Buylla, A. The glial nature of embryonic and adult neural stem cells. Annu. Rev. Neurosci. 32, 149–184 (2009).
Lehre, K.P., Levy, L.M., Ottersen, O.P., Storm-Mathisen, J. & Danbolt, N.C. Differential expression of two glial glutamate transporters in the rat brain: quantitative and immunocytochemical observations. J. Neurosci. 15, 1835–1853 (1995).
Nagy, J.I., Patel, D., Ochalski, P.A. & Stelmack, G.L. Connexin30 in rodent, cat and human brain: selective expression in gray matter astrocytes, co-localization with connexin43 at gap junctions and late developmental appearance. Neuroscience 88, 447–468 (1999).
Poopalasundaram, S. et al. Glial heterogeneity in expression of the inwardly rectifying K(+) channel, Kir4.1, in adult rat CNS. Glia 30, 362–372 (2000).
Bachoo, R.M. et al. Molecular diversity of astrocytes with implications for neurological disorders. Proc. Natl. Acad. Sci. USA 101, 8384–8389 (2004).
Cahoy, J.D. et al. A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J. Neurosci. 28, 264–278 (2008).
Hamby, M.E. et al. Inflammatory mediators alter the astrocyte transcriptome and calcium signaling elicited by multiple G protein–coupled receptors. J. Neurosci. 32, 14489–14510 (2012).
Zamanian, J.L. et al. Genomic analysis of reactive astrogliosis. J. Neurosci. 32, 6391–6410 (2012).
Zhang, Y. et al. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J. Neurosci. 34, 11929–11947 (2014).
Sosunov, A.A. et al. Phenotypic heterogeneity and plasticity of isocortical and hippocampal astrocytes in the human brain. J. Neurosci. 34, 2285–2298 (2014).
Garcia, A.D., Petrova, R., Eng, L. & Joyner, A.L. Sonic hedgehog regulates discrete populations of astrocytes in the adult mouse forebrain. J. Neurosci. 30, 13597–13608 (2010).
Molofsky, A.V. et al. Astrocyte-encoded positional cues maintain sensorimotor circuit integrity. Nature 509, 189–194 (2014).
Bayraktar, O.A., Fuentealba, L.C., Alvarez-Buylla, A. & Rowitch, D.H. Astrocyte development and heterogeneity. Cold Spring Harb. Perspect. Biol. 7, a020362 (2015).
Oliet, S.H. & Bonfardin, V.D. Morphological plasticity of the rat supraoptic nucleus–cellular consequences. Eur. J. Neurosci. 32, 1989–1994 (2010).
Reichenbach, A. & Wolburg, H. Astrocytes and ependymal glia. in Neuroglia 3rd edn. (eds. Kettenmann, H. & Ransom, B.R.) Ch. 4 (Oxford University Press, 2013).
Bernardinelli, Y., Muller, D. & Nikonenko, I. Astrocyte-synapse structural plasticity. Neural Plast. 2014, 232105 (2014).
Sun, D. & Jakobs, T.C. Structural remodeling of astrocytes in the injured CNS. Neuroscientist 18, 567–588 (2012).
Bushong, E.A., Martone, M.E., Jones, Y.Z. & Ellisman, M.H. Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains. J. Neurosci. 22, 183–192 (2002).
Ogata, K. & Kosaka, T. Structural and quantitative analysis of astrocytes in the mouse hippocampus. Neuroscience 113, 221–233 (2002).
Reeves, A.M., Shigetomi, E. & Khakh, B.S. Bulk loading of calcium indicator dyes to study astrocyte physiology: key limitations and improvements using morphological maps. J. Neurosci. 31, 9353–9358 (2011).
Kosaka, T. & Hama, K. Three-dimensional structure of astrocytes in the rat dentate gyrus. J. Comp. Neurol. 249, 242–260 (1986).
Ventura, R. & Harris, K.M. Three-dimensional relationships between hippocampal synapses and astrocytes. J. Neurosci. 19, 6897–6906 (1999).
Witcher, M.R., Kirov, S.A. & Harris, K.M. Plasticity of perisynaptic astroglia during synaptogenesis in the mature rat hippocampus. Glia 55, 13–23 (2007).
Bourne, J.N. & Harris, K.M. Balancing structure and function at hippocampal dendritic spines. Annu. Rev. Neurosci. 31, 47–67 (2008).
Bernardinelli, Y. et al. Activity-dependent structural plasticity of perisynaptic astrocytic domains promotes excitatory synapse stability. Curr. Biol. 24, 1679–1688 (2014).
Lushnikova, I., Skibo, G., Muller, D. & Nikonenko, I. Synaptic potentiation induces increased glial coverage of excitatory synapses in CA1 hippocampus. Hippocampus 19, 753–762 (2009).
Genoud, C. et al. Plasticity of astrocytic coverage and glutamate transporter expression in adult mouse cortex. PLoS Biol. 4, 343 (2006).
Perez-Alvarez, A., Navarrete, M., Covelo, A., Martin, E.D. & Araque, A. Structural and functional plasticity of astrocyte processes and dendritic spine interactions. J. Neurosci. 34, 12738–12744 (2014).
Molotkov, D., Zobova, S., Arcas, J.M. & Khiroug, L. Calcium-induced outgrowth of astrocytic peripheral processes requires actin binding by Profilin-1. Cell Calcium 53, 338–348 (2013).
Lavialle, M. et al. Structural plasticity of perisynaptic astrocyte processes involves ezrin and metabotropic glutamate receptors. Proc. Natl. Acad. Sci. USA 108, 12915–12919 (2011).
Cornell-Bell, A.H., Thomas, P.G. & Smith, S.J. The excitatory neurotransmitter glutamate causes filopodia formation in cultured hippocampal astrocytes. Glia 3, 322–334 (1990).
Pannasch, U. et al. Connexin 30 sets synaptic strength by controlling astroglial synapse invasion. Nat. Neurosci. 17, 549–558 (2014).
Nishida, H. & Okabe, S. Direct astrocytic contacts regulate local maturation of dendritic spines. J. Neurosci. 27, 331–340 (2007).
Stork, T., Sheehan, A., Tasdemir-Yilmaz, O.E. & Freeman, M.R. Neuron-glia interactions through the Heartless FGF receptor signaling pathway mediate morphogenesis of Drosophila astrocytes. Neuron 83, 388–403 (2014).
Morel, L., Higashimori, H., Tolman, M. & Yang, Y. VGluT1+ neuronal glutamatergic signaling regulates postnatal developmental maturation of cortical protoplasmic astroglia. J. Neurosci. 34, 10950–10962 (2014).
Iino, M. et al. Glia-synapse interaction through Ca2+-permeable AMPA receptors in Bergmann glia. Science 292, 926–929 (2001).
Saab, A.S. et al. Bergmann glial AMPA receptors are required for fine motor coordination. Science 337, 749–753 (2012).
Petravicz, J., Fiacco, T.A. & McCarthy, K.D. Loss of IP3 receptor-dependent Ca2+ increases in hippocampal astrocytes does not affect baseline CA1 pyramidal neuron synaptic activity. J. Neurosci. 28, 4967–4973 (2008).
Agulhon, C. et al. What is the role of astrocyte calcium in neurophysiology? Neuron 59, 932–946 (2008).
Khakh, B.S. & McCarthy, K.D. Astrocyte calcium signals: from observations to functions and the challenges therein. Cold Spring Harb. Perspect. Biol. 7, a020404 (2015).
Agulhon, C. et al. Calcium signaling and gliotransmission in normal vs. reactive astrocytes. Front. Pharmacol. 3, 139 (2012).
Fiacco, T.A., Agulhon, C. & McCarthy, K.D. Sorting out astrocyte physiology from pharmacology. Annu. Rev. Pharmacol. Toxicol. 49, 151–174 (2009).
Smith, S.J. Neural signaling. Neuromodulatory astrocytes. Curr. Biol. 4, 807–810 (1994).
Smith, S.J. Do astrocytes process neural information? Prog. Brain Res. 94, 119–136 (1992).
Cornell-Bell, A.H., Finkbeiner, S.M., Cooper, M.S. & Smith, S.J. Glutamate induces calcium waves in cultured astrocytes: long-range glial signaling. Science 247, 470–473 (1990).
Chen, T.W. et al. Ultrasensitive fluorescent proteins for imaging neuronal activity. Nature 499, 295–300 (2013).
Hires, S.A., Tian, L. & Looger, L.L. Reporting neural activity with genetically encoded calcium indicators. Brain Cell Biol. 36, 69–86 (2008).
Tian, L. et al. Imaging neural activity in worms, flies and mice with improved GCaMP calcium indicators. Nat. Methods 6, 875–881 (2009).
Shigetomi, E. et al. Imaging calcium microdomains within entire astrocyte territories and endfeet with GCaMPs expressed using adeno-associated viruses. J. Gen. Physiol. 141, 633–647 (2013).
Shigetomi, E., Kracun, S., Sofroniew, M.V. & Khakh, B.S. A genetically targeted optical sensor to monitor calcium signals in astrocyte processes. Nat. Neurosci. 13, 759–766 (2010).
Shigetomi, E., Tong, X., Kwan, K.Y., Corey, D.P. & Khakh, B.S. TRPA1 channels regulate astrocyte resting calcium and inhibitory synapse efficacy through GAT-3. Nat. Neurosci. 15, 70–80 (2012).
Haustein, M.D. et al. Conditions and constraints for astrocyte calcium signaling in the hippocampal mossy fiber pathway. Neuron 82, 413–429 (2014).
Srinivasan, R. et al. Ca2+ signaling in astrocytes from IP3R2−/− mice in brain slices and during startle responses in vivo. Nat. Neurosci. 18, 708–717 (2015).
Shigetomi, E., Kracun, S. & Khakh, B.S. Monitoring astrocyte calcium microdomains with improved membrane targeted GCaMP reporters. Neuron Glia Biol. 6, 183–191 (2010).
Paukert, M. et al. Norepinephrine controls astroglial responsiveness to local circuit activity. Neuron 82, 1263–1270 (2014).
Panatier, A. et al. Astrocytes are endogenous regulators of basal transmission at central synapses. Cell 146, 785–798 (2011).
Di Castro, M.A. et al. Local Ca2+ detection and modulation of synaptic release by astrocytes. Nat. Neurosci. 14, 1276–1284 (2011).
Straub, S.V., Bonev, A.D., Wilkerson, M.K. & Nelson, M.T. Dynamic inositol trisphosphate–mediated calcium signals within astrocytic endfeet underlie vasodilation of cerebral arterioles. J. Gen. Physiol. 128, 659–669 (2006).
Dunn, K.M., Hill-Eubanks, D.C., Liedtke, W.B. & Nelson, M.T. TRPV4 channels stimulate Ca2+-induced Ca2+ release in astrocytic endfeet and amplify neurovascular coupling responses. Proc. Natl. Acad. Sci. USA 110, 6157–6162 (2013).
Ding, F. α1-Adrenergic receptors mediate coordinated Ca(2+) signaling of cortical astrocytes in awake, behaving mice. Cell Calcium 54, 387–394 (2013).
Kanemaru, K. et al. In vivo visualization of subtle, transient, and local activity of astrocytes using an ultrasensitive Ca(2+) indicator. Cell Reports 8, 311–318 (2014).
Nimmerjahn, A. & Bergles, D.E. Large-scale recording of astrocyte activity. Curr. Opin. Neurobiol. 32C, 95–106 (2015).
Araque, A. et al. Gliotransmitters travel in time and space. Neuron 81, 728–739 (2014).
Hamilton, N.B. & Attwell, D. Do astrocytes really exocytose neurotransmitters? Nat. Rev. Neurosci. 11, 227–238 (2010).
Attwell, D. et al. Glial and neuronal control of brain blood flow. Nature 468, 232–243 (2010).
Clarke, L.E. & Barres, B.A. Emerging roles of astrocytes in neural circuit development. Nat. Rev. Neurosci. 14, 311–321 (2013).
Eroglu, C. & Barres, B.A. Regulation of synaptic connectivity by glia. Nature 468, 223–231 (2010).
Allen, N.J. Astrocyte regulation of synaptic behavior. Annu. Rev. Cell Dev. Biol. 30, 439–463 (2014).
Filosa, J.A. et al. Local potassium signaling couples neuronal activity to vasodilation in the brain. Nat Neurosci. 9, 1397–1403 (2006).
Nimmerjahn, A., Mukamel, E.A. & Schnitzer, M.J. Motor behavior activates Bergmann glial networks. Neuron 62, 400–412 (2009).
Sasaki, T., Matsuki, N. & Ikegaya, Y. Action-potential modulation during axonal conduction. Science 331, 599–601 (2011).
Sasaki, T. et al. Astrocyte calcium signalling orchestrates neuronal synchronization in organotypic hippocampal slices. J. Physiol. (Lond.) 592, 2771–2783 (2014).
Poskanzer, K.E. & Yuste, R. Astrocytic regulation of cortical UP states. Proc. Natl. Acad. Sci. USA 108, 18453–18458 (2011).
Sofroniew, M.V. Astrogliosis. Cold Spring Harb. Perspect. Biol. 7, a020420 (2015).
Agulhon, C., Fiacco, T.A. & McCarthy, K.D. Hippocampal short- and long-term plasticity are not modulated by astrocyte Ca2+ signaling. Science 327, 1250–1254 (2010).
Shepherd, G.M. & Grillner, S. Introduction. in Handbook of Brain Microcircuits. (eds. Grillner, S. & Shepherd, G.M.) xvii (Oxford University Press, 2010).
Henneberger, C., Papouin, T., Oliet, S.H. & Rusakov, D.A. Long-term potentiation depends on release of D-serine from astrocytes. Nature 463, 232–236 (2010).
Shigetomi, E., Jackson-Weaver, O., Huckstepp, R.T., O'Dell, T.J. & Khakh, B.S. TRPA1 channels are regulators of astrocyte basal calcium levels and long-term potentiation via constitutive D-serine release. J. Neurosci. 33, 10143–10153 (2013).
Grosche, J. et al. Microdomains for neuron-glia interaction: parallel fiber signaling to Bergmann glial cells. Nat. Neurosci. 2, 139–143 (1999).
Kerr, J.N. & Nimmerjahn, A. Functional imaging in freely moving animals. Curr. Opin. Neurobiol. 22, 45–53 (2012).
Kang, J. et al. Connexin 43 hemichannels are permeable to ATP. J. Neurosci. 28, 4702–4711 (2008).
Bekar, L.K., He, W. & Nedergaard, M. Locus coeruleus alpha-adrenergic-mediated activation of cortical astrocytes in vivo. Cereb. Cortex 18, 2789–2795 (2008).
Christian, C.A. et al. Endogenous positive allosteric modulation of GABA(A) receptors by diazepam binding inhibitor. Neuron 78, 1063–1074 (2013).
Christian, C.A. & Huguenard, J.R. Astrocytes potentiate GABAergic transmission in the thalamic reticular nucleus via endozepine signaling. Proc. Natl. Acad. Sci. USA 110, 20278–20283 (2013).
Gourine, A.V. et al. Astrocytes control breathing through pH-dependent release of ATP. Science 329, 571–575 (2010).
Tsai, H.H. et al. Regional astrocyte allocation regulates CNS synaptogenesis and repair. Science 337, 358–362 (2012).
Hochstim, C., Deneen, B., Lukaszewicz, A., Zhou, Q. & Anderson, D.J. Identification of positionally distinct astrocyte subtypes whose identities are specified by a homeodomain code. Cell 133, 510–522 (2008).
Fatatis, A., Holtzclaw, L.A., Avidor, R., Brenneman, D.E. & Russell, J.T. Vasoactive intestinal peptide increases intracellular calcium in astroglia: synergism with alpha-adrenergic receptors. Proc. Natl. Acad. Sci. USA 91, 2036–2040 (1994).
Takata, N. et al. Astrocyte calcium signaling transforms cholinergic modulation to cortical plasticity in vivo. J. Neurosci. 31, 18155–18165 (2011).
Navarrete, M. et al. Astrocytes mediate in vivo cholinergic-induced synaptic plasticity. PLoS Biol. 10, e1001259 (2012).
Sofroniew, M.V. Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci. 32, 638–647 (2009).
Burda, J.E. & Sofroniew, M.V. Reactive gliosis and the multicellular response to CNS damage and disease. Neuron 81, 229–248 (2014).
Bradford, J. et al. Expression of mutant huntingtin in mouse brain astrocytes causes age-dependent neurological symptoms. Proc. Natl. Acad. Sci. USA 106, 22480–22485 (2009).
Tong, X. et al. Astrocyte Kir4.1 ion channel deficits contribute to neuronal dysfunction in Huntington's disease model mice. Nat. Neurosci. 17, 694–703 (2014).
Estrada-Sánchez, A.M. & Rebec, G.V. Corticostriatal dysfunction and glutamate transporter 1 (GLT1) in Huntington's disease: interactions between neurons and astrocytes. Basal Ganglia 2, 57–66 (2012).
Kofuji, P. & Newman, E.A. Potassium buffering in the central nervous system. Neuroscience 129, 1045–1056 (2004).
Cepeda, C., Cummings, D.M., André, V.M., Holley, S.M. & Levine, M.S. Genetic mouse models of Huntington's disease: focus on electrophysiological mechanisms. ASN Neuro. 2, e00033 (2010).
Kuchibhotla, K.V., Lattarulo, C.R., Hyman, B.T. & Bacskai, B.J. Synchronous hyperactivity and intercellular calcium waves in astrocytes in Alzheimer mice. Science 323, 1211–1215 (2009).
Delekate, A. et al. Metabotropic P2Y1 receptor signalling mediates astrocytic hyperactivity in vivo in an Alzheimer's disease mouse model. Nat. Commun. 5, 5422 (2014).
Kang, W. & Hebert, J.M. Signaling pathways in reactive astrocytes, a genetic perspective. Mol. Neurobiol. 43, 147–154 (2011).
Pekny, M. & Pekna, M. Astrocyte reactivity and reactive astrogliosis: costs and benefits. Physiol. Rev. 94, 1077–1098 (2014).
Wanner, I.B. et al. Glial scar borders are formed by newly proliferated, elongated astrocytes that interact to corral inflammatory and fibrotic cells via STAT3-dependent mechanisms after spinal cord injury. J. Neurosci. 33, 12870–12886 (2013).
Anderson, M.A., Ao, Y. & Sofroniew, M.V. Heterogeneity of reactive astrocytes. Neurosci. Lett. 565, 23–29 (2014).
Sofroniew, M.V. Astrocyte barriers to neurotoxic inflammation. Nat. Rev. Neurosci. 16, 249–263 (2015).
Bush, T.G. et al. Leukocyte infiltration, neuronal degeneration, and neurite outgrowth after ablation of scar-forming, reactive astrocytes in adult transgenic mice. Neuron 23, 297–308 (1999).
Myer, D.J., Gurkoff, G.G., Lee, S.M., Hovda, D.A. & Sofroniew, M.V. Essential protective roles of reactive astrocytes in traumatic brain injury. Brain 129, 2761–2772 (2006).
Bardehle, S. et al. Live imaging of astrocyte responses to acute injury reveals selective juxtavascular proliferation. Nat. Neurosci. 16, 580–586 (2013).
Benner, E.J. et al. Protective astrogenesis from the SVZ niche after injury is controlled by Notch modulator Thbs4. Nature 497, 369–373 (2013).
Barnabé-Heider, F. et al. Origin of new glial cells in intact and injured adult spinal cord. Cell Stem Cell 7, 470–482 (2010).
Nimmerjahn, A., Kirchhoff, F. & Helmchen, F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308, 1314–1318 (2005).
Wilhelmsson, U. et al. Redefining the concept of reactive astrocytes as cells that remain within their unique domains upon reaction to injury. Proc. Natl. Acad. Sci. USA 103, 17513–17518 (2006).
Rao, V.L., Bowen, K.K. & Dempsey, R.J. Transient focal cerebral ischemia down-regulates glutamate transporters GLT-1 and EAAC1 expression in rat brain. Neurochem. Res. 26, 497–502 (2001).
Olsen, M.L. & Sontheimer, H. Functional implications for Kir4.1 channels in glial biology: from K+ buffering to cell differentiation. J. Neurochem. 107, 589–601 (2008).
Ortinski, P.I. et al. Selective induction of astrocytic gliosis generates deficits in neuronal inhibition. Nat. Neurosci. 13, 584–591 (2010).
Han, X. et al. Forebrain engraftment by human glial progenitor cells enhances synaptic plasticity and learning in adult mice. Cell Stem Cell 12, 342–353 (2013).
Lancaster, M.A. & Knoblich, J.A. Organogenesis in a dish: modeling development and disease using organoid technologies. Science 345, 1247125 (2014).
Kepecs, A. & Fishell, G. Interneuron cell types are fit to function. Nature 505, 318–326 (2014).
Martone, M.E. et al. A cell centered database for electron tomographic data. J. Struct. Biol. 138, 145–155 (2002).
Bushong, E.A., Martone, M.E. & Ellisman, M.H. Maturation of astrocyte morphology and the establishment of astrocyte domains during postnatal hippocampal development. Int. J. Dev. Neurosci. 22, 73–86 (2004).
Bonder, D.E. & McCarthy, K.D. Astrocytic Gq-GPCR–linked IP3R-dependent Ca2+ signaling does not mediate neurovascular coupling in mouse visual cortex in vivo. J. Neurosci. 34, 13139–13150 (2014).
Jiang, R., Haustein, M.D., Sofroniew, M.V. & Khakh, B.S. Imaging intracellular Ca2+ signals in striatal astrocytes from adult mice using genetically-encoded calcium indicators. J. Vis. Exp. doi:10.3791/51972 (19 November 2014).
Zariwala, H.A. et al. A Cre-dependent GCaMP3 reporter mouse for neuronal imaging in vivo. J. Neurosci. 32, 3131–3141 (2012).
Gee, J.M. et al. Imaging activity in neurons and glia with a Polr2a-based and cre-dependent GCaMP5G-IRES-tdTomato reporter mouse. Neuron 83, 1058–1072 (2014).
Atkin, S.D. et al. Transgenic mice expressing a cameleon fluorescent Ca2+ indicator in astrocytes and Schwann cells allow study of glial cell Ca2+ signals in situ and in vivo. J. Neurosci. Methods 181, 212–226 (2009).
Madisen, L. et al. Transgenic mice for intersectional targeting of neural sensors and effectors with high specificity and performance. Neuron 85, 942–958 (2015).
Acknowledgements
B.S.K. is supported by the US National Institutes of Health (NIH; NS060677, MH099559A, MH104069) and the CHDI Foundation. M.V.S. is supported by NIH (NS084030), Wings for Life, Hilton Foundation, CHDI, and the Dr. Miriam and Sheldon B. Adelson Medical Research Foundation. The images shown in Figure 1 are from the The Cell Centered Database, which is supported by NIH grants from NCRR RR04050, RR RR08605, and the Human Brain Project DA016602 from the National Institute on Drug Abuse, the National Institute of Biomedical Imaging and Bioengineering, and the National Institute of Mental Health.
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Khakh, B., Sofroniew, M. Diversity of astrocyte functions and phenotypes in neural circuits. Nat Neurosci 18, 942–952 (2015). https://doi.org/10.1038/nn.4043
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DOI: https://doi.org/10.1038/nn.4043
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