Abstract
Although much is known about the functional expression of the neuronal nicotinic acetylcholine receptors (nAChRs) in various neuronal populations in the brain and elsewhere, much less is known about their expression and functional relevance in glial cells. The expression of functional nAChRs has been reported for cultured astrocytes; however, previous work has failed to detect nAChR-mediated responses in astrocytes in acute slices. In the current study, functional α7 nAChRs on astrocytes in the CA1 region of the rat hippocampus were studied in situ using whole-cell patch-clamp recording and two-photon calcium imaging techniques in acute slices. We found that astrocytes and the chondroitin sulfate proteoglycan NG2-expressing (i.e., NG2) cells did express functional α7 nAChRs. Although the amplitudes of the responses were small, they could be enhanced by the α7-selective positive allosteric modulator PNU-120596. Under these conditions, we found that in comparing the properties of these responses between astrocytes, NG2, and interneurons, there were differences in the kinetics and increases in intracellular calcium levels. This is the first demonstration of functional α7 nAChR-mediated current responses in astrocytes in acute hippocampal slices, data which may shed light on the role of α7 nAChRs in neuroprotection.
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Agulhon C, Petravicz J, McMullen AB, Sweger EJ, Minton SK, Taves SR, Casper KB, Fiacco TA, McCarthy KD (2008) What is the role of astrocyte calcium in neurophysiology? Neuron 59:932–946
Araque A, Martín ED, Perea G, Arellano JI, Buño W (2002) Synaptically released acetylcholine evokes Ca2+ elevations in astrocytes in hippocampal slices. J Neurosci 22:2443–2450
Cobb SR, Davies CH (2005) Cholinergic modulation of hippocampal cells and circuits. J Physiol (Lond) 562:81–88
Dajas-Bailador FA, Lima PA, Wonnacott S (2000) The α7 nicotinic acetylcholine receptor subtype mediates nicotine protection against NMDA excitotoxicity in primary hippocampal cultures through a Ca2+-dependent mechanism. Neuropharmacol 39:2799–2807
Dani JA, Bertrand D (2007) Nicotinic acetylcholine receptors and nicotinic cholinergic mechanisms of the central nervous system. Annu Rev Pharmacol Toxicol 47:699–729
Dineley KT (2007) Beta-amyloid peptide—nicotinic acetylcholine receptor interaction: the two faces of health and disease. Front Biosci 12:5030–5038
Dziewczapolski G, Glogowski CM, Masliah E, Heinemann SF (2009) Deletion of the α7 nicotinic acetylcholine receptor gene improves cognitive deficits and synaptic pathology in a mouse model of Alzheimer’s disease. J Neurosci 29:8805–8815
Fiacco TA, Agulhon C, McCarthy KD (2009) Sorting out astrocyte physiology from pharmacology. Annu Rev Pharmacol Toxicol 49:151–74
Frazier CJ, Rollins YD, Breese CR, Leonard S, Freedman R, Dunwiddie TV (1998) Acetylcholine activates an α-bungarotoxin-sensitive nicotinic current in rat hippocampal interneurons, but not pyramidal cells. J Neurosci 18:1187–1195
Frotscher M, Léránth C (1985) Cholinergic innervation of the rat hippocampus as revealed by choline acetyltransferase immunocytochemistry: a combined light and electron microscopic study. J Comp Neurol 239:237–246
Fucile S, Sucapane A, Grassi F, Eusebi F, Engel AG (2006) The human adult subtype ACh receptor channel has high Ca2+ permeability and predisposes to endplate Ca2+ overloading. J Physiol (Lond) 573:35–43
Fujii S, Sumikawa K (2001) Nicotine accelerates reversal of long-term potentiation and enhances long-term depression in the rat hippocampal CA1 region. Brain Res 894:340–346
Gay EA, Yakel JL (2007) Gating of nicotinic ACh receptors; new insights into structural transitions triggered by agonist binding that induce channel opening. J Physiology (Topical Review) 584:727–733
Giniatullin R, Nistri A, Yakel JL (2005) Desensitization of nicotinic ACh receptors: shaping cholinergic signaling. Trends Neurosci 28:371–378
Gu Z, Yakel JL (2011) Timing-dependent septal cholinergic induction of dynamic hippocampal synaptic plasticity. Neuron 71:155–165
Henneberger C, Papouin T, Oliet SH, Rusakov DA (2010) Long-term potentiation depends on release of d-serine from astrocytes. Nature 463:232–236
Hernandez CM, Kayed R, Zheng H, Sweatt JD, Dineley KT (2010) Loss of α7 nicotinic receptors enhances beta-amyloid oligomer accumulation, exacerbating early-stage cognitive decline and septo-hippocampal pathology in a mouse model of Alzheimer’s disease. J Neurosci 30:2442–2453
Ji D, Lape R, Dani JA (2001) Timing and location of nicotinic activity enhances or depresses hippocampal synaptic plasticity. Neuron 31:131–141
Jones S, Sudweeks S, Yakel JL (1999) Nicotinic receptors in the brain: correlating physiology with function. Trends Neurosci 22:555–561
Jonnala RR, Buccafusco JJ (2001) Relationship between the increased cell surface α7 nicotinic receptor expression and neuroprotection induced by several nicotinic receptor agonists. J Neurosci Res 66:565–572
Kafitz KW, Meier SD, Stephan J, Rose CR (2008) Developmental profile and properties of sulforhodamine 101—labeled glial cells in acute brain slices of rat hippocampus. J Neurosci Methods 169:84–92
Kang J, Jiang L, Goldman SA, Nedergaard M (1998) Astrocyte-mediated potentiation of inhibitory synaptic transmission. Nat Neurosci 1:683–92
Kihara T, Shimohama S, Sawada H, Kimura J, Kume T, Kochiyama H, Maeda T, Akaike A (1997) Nicotinic receptor stimulation protects neurons against beta-amyloid toxicity. Ann Neurol 42:159–163
Kihara T, Shimohama S, Sawada H, Honda K, Nakamizo T, Shibasaki H, Kume T, Akaike A (2001) Alpha 7 nicotinic receptor transduces signals to phosphatidylinositol 3-kinase to block A beta-amyloid-induced neurotoxicity. J Biol Chem 276:13541–13546
Khiroug L, Giniatullin R, Klein RC, Fayuk D, Yakel JL (2003) Functional mapping and Ca2+ regulation of nicotinic acetylcholine receptor channels in rat hippocampal CA1 neurons. J Neurosci 23:9024–9031
Levin ED (2002) Nicotinic receptor subtypes and cognitive function. J Neurobiol 53:633–640
Levin ED, McClernon FJ, Rezvani AH (2006) Nicotinic effects on cognitive function: behavioral characterization, pharmacological specification, and anatomic localization. Psychopharmacology (Berl) 184:523–539
Levin ED, Petro A, Rezvani AH, Pollard N, Christopher NC, Strauss M, Avery J, Nicholson J, Rose JE (2009) Nicotinic α7- or β2-containing receptor knockout: effects on radial-arm maze learning and long-term nicotine consumption in mice. Behav Brain Res 196:207–213
Lin SC, Bergles DE (2004) Synaptic signaling between neurons and glia. Glia 47:290–298
Lukas RJ, Lucero L, Buisson B, Galzi JL, Puchacz E, Fryer JD, Changeux JP, Bertrand D (2001) Neurotoxicity of channel mutations in heterologously expressed α7-nicotinic acetylcholine receptors. Eur J Neurosci 13:1849–1860
McGehee DS (2002) Nicotinic receptors and hippocampal synaptic plasticity … it’s all in the timing. Trends Neurosci 25:171–172
Nagele RG, D’Andrea MR, Lee H, Venkataraman V, Wang HY (2003) Astrocytes accumulate Aβ42 and give rise to astrocytic amyloid plaques in Alzheimer disease brains. Brain Res 971:197–209
Nagele RG, Wegiel J, Venkataraman V, Imaki H, Wang KC, Wegiel J (2004) Contribution of glial cells to the development of amyloid plaques in Alzheimer’s disease. Neurobiol Aging 25:663–674
Ng HJ, Whittemore ER, Tran MB, Hogenkamp DJ, Broide RS, Johnstone TB, Zheng L, Stevens KE, Gee KW (2007) Nootropic α7 nicotinic receptor allosteric modulator derived from GABAA receptor modulators. Proc Natl Acad Sci USA 104:8059–8064
Parri HR, Hernandez CM, Kineley KT (2011) Research update: alpha7 nicotinic acetylcholine receptor mechanisms in Alzheimer’s disease. Biochem Pharmacol 82:931–942
Perea G, Araque A (2005) Properties of synaptically evoked astrocyte calcium signal reveal synaptic information processing by astrocytes. J Neurosci 25:2192–2203
Sharma G, Vijayaraghavan S (2001) Nicotinic cholinergic signaling in hippocampal astrocytes involves calcium-induced calcium release from intracellular stores. Proc Natl Acad Sci USA 98:4148–4153
Shelton MK, McCarthy KD (2000) Hippocampal astrocytes exhibit Ca2+-elevating muscarinic cholinergic and histaminergic receptors in situ. J Neurochem 74:555–563
Shen JX, Tu B, Yakel JL (2009) Inhibition of α7-containing nicotinic ACh receptors by muscarinic M1 ACh receptors in rat hippocampal CA1 interneurones in slices. J Physiol 587:1033–1042
Shytle RD, Mori T, Townsend K, Vendrame M, Sun N, Zeng J, Ehrhart J, Silver AA, Sanberg PR, Tan J (2004) Cholinergic modulation of microglial activation by alpha 7 nicotinic receptors. J Neurochem 89:337–343
Stevens TR, Krueger SR, Fitzsimonds RM, Picciotto MR (2003) Neuroprotection by nicotine in mouse primary cortical cultures involves activation of calcineurin and L-type calcium channel inactivation. J Neurosci 23:10093–10099
Sudweeks SN, Hooft JA, Yakel JL (2002) Serotonin 5-HT3 receptors in rat CA1 hippocampal interneurons: functional and molecular characterization. J Physiol 544:715–726
Svensson AL, Nordberg A (1999) Beta-estradiol attenuate amyloid beta-peptide toxicity via nicotinic receptors. Neuroreport 10:3485–3489
Teaktong T, Graham A, Court J, Perry R, Jaros E, Johnson M, Hall R, Perry E (2003) Alzheimer’s disease is associated with a selective increase in alpha7 nicotinic acetylcholine receptor immunoreactivity in astrocytes. Glia 41:207–211
Tyagi E, Agrawal R, Nath C, Shukla R (2010) Inhibitory role of cholinergic system mediated via α7 nicotinic acetylcholine receptor in LPS-induced neuro-inflammation. Innate Immun 16:3–13
Vélez-Fort M, Audinat E, Angulo MC (2009) Functional alpha 7-containing nicotinic receptors of NG2-expressing cells in the hippocampus. Glia 57:1104–1114
Wang H, Yu M, Ochani M, Amella CA, Tanovic M, Susarla S, Li JH, Wang H, Yang H, Ulloa L, Al-Abed Y, Czura CJ, Tracey KJ (2003) Nicotinic acetylcholine receptor α7 subunit is an essential regulator of inflammation. Nature 421:384–388
Xiu J, Nordberg A, Zhang JT, Guan ZZ (2005) Expression of nicotinic receptors on primary cultures of rat astrocytes and upregulation of the α7, α4 and β2 subunits in response to nanomolar concentrations of the β-amyloid peptide1–42. Neurochem Int 47:281–290
Yakel JL (2010) Gating of nicotinic ACh receptors: latest insights into ligand binding and function. J Physiology (Symposium Review) 588:597–602
Yu WF, Guan ZZ, Bogdanovic N, Nordberg A (2005) High selective expression of α7 nicotinic receptors on astrocytes in the brains of patients with sporadic Alzheimer’s disease and patients carrying Swedish APP 670/671 mutation: a possible association with neuritic plaques. Exp Neurol 192:215–225
Acknowledgements
We would like to thank C. Erxleben for the advice in preparing the manuscript. Research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. Further support was provided to Jian-xin Shen by the National Natural Science Foundation of China (No. 31171089).
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Shen, Jx., Yakel, J.L. Functional α7 Nicotinic ACh Receptors on Astrocytes in Rat Hippocampal CA1 Slices. J Mol Neurosci 48, 14–21 (2012). https://doi.org/10.1007/s12031-012-9719-3
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DOI: https://doi.org/10.1007/s12031-012-9719-3