Abstract
Excitatory amino-acid transporters (EAATs) bind and transport glutamate, limiting spillover from synapses due to their dense perisynaptic expression primarily on astroglia. Converging evidence suggests that abnormalities in the astroglial glutamate transporter localization and function may underlie a disease mechanism with pathological glutamate spillover as well as alterations in the kinetics of perisynaptic glutamate buffering and uptake contributing to dysfunction of thalamo-cortical circuits in schizophrenia. We explored this hypothesis by performing cell- and region-level studies of EAAT1 and EAAT2 expression in the mediodorsal nucleus of the thalamus in an elderly cohort of subjects with schizophrenia. We found decreased protein expression for the typically astroglial-localized glutamate transporters in the mediodorsal and ventral tier nuclei. We next used laser-capture microdissection and quantitative polymerase chain reaction to assess cell-level expression of the transporters and their splice variants. In the mediodorsal nucleus, we found lower expression of transporter transcripts in a population of cells enriched for astrocytes, and higher expression of transporter transcripts in a population of cells enriched for relay neurons. We confirmed expression of transporter protein in neurons in schizophrenia using dual-label immunofluorescence. Finally, the pattern of transporter mRNA and protein expression in rodents treated for 9 months with antipsychotic medication suggests that our findings are not due to the effects of antipsychotic treatment. We found a compensatory increase in transporter expression in neurons that might be secondary to a loss of transporter expression in astrocytes. These changes suggest a profound abnormality in astrocyte functions that support, nourish and maintain neuronal fidelity and synaptic activity.
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References
Steriade M, Jones EG, McCormick DA (eds). The Thalamus. Elsevier: Oxford, 1997.
Alelu-Paz R, Gimenez-Amaya JM . The mediodorsal thalamic nucleus and schizophrenia. J Psychiatry Neurosci 2008; 33: 489–498.
Briggs F, Usrey WM . Emerging views of corticothalamic function. Curr Opin Neurobiol 2008; 18: 403–407.
Russchen FT, Amaral DG, Price JL . The afferent input to the magnocellular division of the mediodorsal thalamic nucleus in the monkey, Macaca fascicularis. J Comp Neurol 1987; 256: 175–210.
Cummings JL . Anatomic and behavioral aspects of frontalsubcortical circuits. In: Grafman J, Holyoak KJ, Boller F (eds). Structures and Functions of the Human Prefrontal Cortex, vol. 769. New York Academy of Sciences: New York, 1995, pp 1–13.
Andreasen NC, Arndt S, Swayze V 2nd, Cizadlo T, Flaum M, O'Leary D et al. Thalamic abnormalities in schizophrenia visualized through magnetic resonance image averaging. Science 1994; 266: 294–298.
Jones EG . Cortical development and thalamic pathology in schizophrenia. Schizophr Bull 1997; 23: 483–501.
Jones EG . A new view of specific and nonspecific thalamocortical connections. Adv Neurol 1998; 77: 49–71.
Dorph-Petersen KA, Pierri JN, Sun Z, Sampson AR, Lewis DA . Stereological analysis of the mediodorsal thalamic nucleus in schizophrenia: volume, neuron number, and cell types. J Comp Neurol 2004; 472:: 449–462.
Torrey EF, Peterson MR . Schizophrenia and the limbic system. Lancet 1974; 2: 942–946.
Ferrarelli F, Sarasso S, Guller Y, Riedner BA, Peterson MJ, Bellesi M et al. Reduced natural oscillatory frequency of frontal thalamocortical circuits in schizophrenia. Arch Gen Psychiatry 2012; 69: 766–774.
Guller Y, Ferrarelli F, Shackman AJ, Sarasso S, Peterson MJ, Langheim FJ et al. Probing thalamic integrity in schizophrenia using concurrent transcranial magnetic stimulation and functional magnetic resonance imaging. Arch Gen Psychiatry 2012; 69: 662–671.
Woodward ND, Karbasforoushan H, Heckers S . Thalamocortical dysconnectivity in schizophrenia. Am J Psychiatry 2012; 169: 1092–1099.
Sodhi MS, Simmons M, McCullumsmith R, Haroutunian V, Meador- Woodruff JH . Glutamatergic gene expression is specifically reduced in thalamocortical projecting relay neurons in schizophrenia. Biol Psychiatry 2011; 70: 646–654.
Smith RE, Haroutunian V, Davis KL, Meador-Woodruff JH . Expression of excitatory amino acid transporter transcripts in the thalamus of subjects with schizophrenia. Am J Psychiatry 2001; 158: 1393–1399.
Lauriat TL, McInnes LA . EAAT2 regulation and splicing: relevance to psychiatric and neurological disorders. Mol Psychiatry 2007; 12: 1065–1078.
Dekaban A . Human thalamus; an anatomical, developmental and pathological study. I. Division of the human adult thalamus into nuclei by use of the cyto-myelo-architectonic method. J Comp Neurol 1953; 99: 639–683.
Shan D, Haroutunian V, Meador-Woodruff JH, McCullumsmith RE . Expression of equilibrative nucleoside transporter type 1 protein in elderly patients with schizophrenia. Neuroreport 2012; 23: 224–227.
Shan D, Mount D, Moore S, Haroutunian V, Meador-Woodruff JH, McCullumsmith RE . Abnormal partitioning of hexokinase 1 suggests disruption of a glutamate transport protein complex in schizophrenia. Schizophr Res 2014; 154: 1–13.
Morel A, Magnin M, Jeanmonod D . Multiarchitectonic and stereotactic atlas of the human thalamus. J Comp Neurol 1997; 387: 588–630.
Smith RE, Haroutunian V, Davis KL, Meador-Woodruff JH . Vesicular glutamate transporter transcript expression in the thalamus in schizophrenia. Neuroreport 2001; 12: 2885–2887.
Chen W, Aoki C, Mahadomrongkul V, Gruber CE, Wang GJ, Blitzblau R et al. Expression of a variant form of the glutamate transporter GLT1 in neuronal cultures and in neurons and astrocytes in the rat brain. J Neurosci 2002; 22: 2142–2152.
Roberts RC, Roche JK, McCullumsmith RE . Localization of excitatory amino acid transporters EAAT1 and EAAT2 in human postmortem cortex: a light and electron microscopic study. Neuroscience 2014; 277: 522–540.
Chaudhry FA, Lehre KP, van Lookeren Campagne M, Ottersen OP, Danbolt NC, Storm-Mathisen J . Glutamate transporters in glial plasma membranes: highly differentiated localizations revealed by quantitative ultrastructural immunocytochemistry. Neuron 1995; 15: 711–720.
Lehre KP, Levy LM, Ottersen OP, Storm-Mathisen J, Danbolt NC . Differential expression of two glial glutamate transporters in the rat brain: quantitative and immunocytochemical observations. J Neurosci 1995; 15: 1835–1853.
Danbolt NC . Glutamate uptake. Prog Neurobiol 2001; 65: 1–105.
Rothstein JD, Dykes-Hoberg M, Pardo CA, Bristol LA, Jin L, Kuncl RW et al. Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron 1996; 16: 675–686.
Tanaka K, Watase K, Manabe T, Yamada K, Watanabe M, Takahashi K et al. Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1. Science 1997; 276: 1699–1702.
Pow DV, Naidoo T, Lingwood BE, Healy GN, Williams SM, Sullivan RK et al. Loss of glial glutamate transporters and induction of neuronal expression of GLT-1B in the hypoxic neonatal pig brain. Brain Res Dev Brain Res 2004; 153: 1–11.
Sullivan SM, Macnab LT, Bjorkman ST, Colditz PB, Pow DV . GLAST1b, the exon-9 skipping form of the glutamate-aspartate transporter EAAT1 is a sensitive marker of neuronal dysfunction in the hypoxic brain. Neuroscience 2007; 149: 434–445.
Philips T, Rothstein JD . Glial cells in amyotrophic lateral sclerosis. Exp Neurol 2014; 262: 111–120.
Rose EM, Koo JC, Antflick JE, Ahmed SM, Angers S, Hampson DR . Glutamate transporter coupling to Na,K-ATPase. J Neurosci 2009; 29: 8143–8155.
Genda EN, Jackson JG, Sheldon AL, Locke SF, Greco TM, O'Donnell JC et al. Co-compartmentalization of the astroglial glutamate transporter, GLT-1, with glycolytic enzymes and mitochondria. J Neurosci 2011; 31: 18275–18288.
Cholet N, Pellerin L, Magistretti PJ, Hamel E . Similar perisynaptic glial localization for the Na+,K+-ATPase alpha 2 subunit and the glutamate transporters GLAST and GLT-1 in the rat somatosensory cortex. Cereb Cortex 2002; 12: 515–525.
Jackson JG, O'Donnell JC, Krizman E, Robinson MB . Displacing hexokinase from mitochondrial voltage-dependent anion channel impairs GLT-1-mediated glutamate uptake but does not disrupt interactions between GLT-1 and mitochondrial proteins. J Neurosci Res 2014; 93: 999–1008.
Bouzier-Sore AK, Pellerin L . Unraveling the complex metabolic nature of astrocytes. Front Cell Neurosci 2013; 7: 179.
Shan D, Lucas EK, Drummond JB, Haroutunian V, Meador-Woodruff JH, McCullumsmith RE . Abnormal expression of glutamate transporters in temporal lobe areas in elderly patients with schizophrenia. Schizophr Res 2013; 144: 1–8.
Shan D, Yates S, Roberts RC, McCullumsmith RE . Update on the neurobiology of schizophrenia: a role for extracellular microdomains. Minerva Psichiatr 2012; 53: 233–249.
Tawfik VL, Regan MR, Haenggeli C, Lacroix-Fralish ML, Nutile-McMenemy N, Perez N et al. Propentofylline-induced astrocyte modulation leads to alterations in glial glutamate promoter activation following spinal nerve transection. Neuroscience 2008; 152: 1086–1092.
Martin LJ, Brambrink AM, Lehmann C, Portera-Cailliau C, Koehler R, Rothstein J et al. Hypoxia-ischemia causes abnormalities in glutamate transporters and death of astroglia and neurons in newborn striatum. Ann Neurol 1997; 42: 335–348.
Cimarosti H, Jones NM, O'Shea RD, Pow DV, Salbego C, Beart PM . Hypoxic preconditioning in neonatal rat brain involves regulation of excitatory amino acid transporter 2 and estrogen receptor alpha. Neurosci Lett 2005; 385: 52–57.
Yi JH, Pow DV, Hazell AS . Early loss of the glutamate transporter splice-variant GLT-1v in rat cerebral cortex following lateral fluid-percussion injury. Glia 2005; 49: 121–133.
Goodrich GS, Kabakov AY, Hameed MQ, Dhamne SC, Rosenberg PA, Rotenberg A . Ceftriaxone treatment after traumatic brain injury restores expression of the glutamate transporter, GLT-1, reduces regional gliosis, and reduces post-traumatic seizures in the rat. J Neurotrauma 2013; 30: 1434–1441.
Maragakis NJ, Dykes-Hoberg M, Rothstein JD . Altered expression of the glutamate transporter EAAT2b in neurological disease. Ann Neurol 2004; 55: 469–477.
McCullumsmith RE . Evidence for schizophrenia as a disorder of neuroplasticity. Am J Psychiatry 2015; 172: 312–313.
Selkirk JV, Stiefel TH, Stone IM, Naeve GS, Foster AC, Poulsen DJ . Over- expression of the human EAAT2 glutamate transporter within neurons of mouse organotypic hippocampal slice cultures leads to increased vulnerability of CA1 pyramidal cells. Eur J Neurosci 2005; 21: 2291–2296.
Lee A, Pow DV . Astrocytes: glutamate transport and alternate splicing of transporters. Int J Biochem Cell Biol 2010; 42: 1901–1906.
Gonzalez-Gonzalez IM, Garcia-Tardon N, Cubelos B, Gimenez C, Zafra F . The glutamate transporter GLT1b interacts with the scaffold protein PSD-95. J Neurochem 2008; 105: 1834–1848.
Feng W, Zhang M . Organization and dynamics of PDZ-domain-related supramodules in the postsynaptic density. Nat Rev Neurosci 2009; 10: 87–99.
Bassan M, Liu H, Madsen KL, Armsen W, Zhou J, Desilva T et al. Interaction between the glutamate transporter GLT1b and the synaptic PDZ domain protein PICK1. Eur J Neurosci 2008; 27: 66–82.
O'Donovan SM, Hassefeld K, Bauer D, Simmons M, Roussos P, Haroutunian V et al. Glutamate transporter splice variant expression in an enriched pyramidal cell population in schizophrenia. Transl Psychiatry 2015; 5: e579.
Hammond JC, McCullumsmith RE, Funk AJ, Haroutunian V, Meador-Woodruff JH . Evidence for abnormal forward trafficking of AMPA receptors in frontal cortex of elderly patients with schizophrenia. Neuropsychopharmacology 2010; 35: 2110–2119.
Kristiansen LV, Bakir B, Haroutunian V, Meador-Woodruff JH . Expression of the NR2B-NMDA receptor trafficking complex in prefrontal cortex from a group of elderly patients with schizophrenia. Schizophr Res 2010; 119: 198–209.
Kristiansen L, Patel S, Haroutunian V, Meador-Woodruff JH . Expression of the NR2B-NMDA receptor subunit and its Tbr-1/CINAP regulatory proteins in postmortem brain suggest altered receptor processing in schizophrenia. Synapse 2010; 64: 495–502.
Bauer D, Gupta D, Harotunian V, Meador-Woodruff JH, McCullumsmith RE . Abnormal expression of glutamate transporter and transporter interacting molecules in prefrontal cortex in elderly patients with schizophrenia. Schizophr Res 2008; 104: 108–120.
Bauer D, Haroutunian V, Meador-Woodruff JH, McCullumsmith RE . Abnormal glycosylation of EAAT1 and EAAT2 in prefrontal cortex of elderly patients with schizophrenia. Schizophr Res 2010; 117: 92–98.
Regan MR, Huang YH, Kim YS, Dykes-Hoberg MI, Jin L, Watkins AM et al. Variations in promoter activity reveal a differential expression and physiology of glutamate transporters by glia in the developing and mature CNS. J Neurosci 2007; 27: 6607–6619.
Karlsson RM, Tanaka K, Saksida LM, Bussey TJ, Heilig M, Holmes A . Assessment of glutamate transporter GLAST (EAAT1)-deficient mice for phenotypes relevant to the negative and executive/cognitive symptoms of schizophrenia. Neuropsychopharmacology 2009; 34: 1578–1589.
Karlsson RM, Tanaka K, Heilig M, Holmes A . Loss of glial glutamate and aspartate transporter (excitatory amino acid transporter 1) causes locomotor hyperactivity and exaggerated responses to psychotomimetics: rescue by haloperidol and metabotropic glutamate 2/3 agonist. Biol Psychiatry 2008; 64: 810–814.
Walsh T, McClellan JM, McCarthy SE, Addington AM, Pierce SB, Cooper GM et al. Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 2008; 320: 539–543.
Scott HA, Gebhardt FM, Mitrovic AD, Vandenberg RJ, Dodd PR . Glutamate transporter variants reduce glutamate uptake in Alzheimer's disease. Neurobiol Aging 2011; 32: 553. e1–e11.
Vallejo-Illarramendi A, Domercq M, Matute C . A novel alternative splicing form of excitatory amino acid transporter 1 is a negative regulator of glutamate uptake. J Neurochem 2005; 95: 341–348.
Pow DV, Cook DG . Neuronal expression of splice variants of "glial" glutamate transporters in brains afflicted by Alzheimer's disease: unmasking an intrinsic neuronal property. Neurochem Res 2009; 34: 1748–1757.
Pakkenberg B, Scheel-Kruger J, Kristiansen LV . Schizophrenia; from structure to function with special focus on the mediodorsal thalamic prefrontal loop. Acta Psychiatr Scand 2009; 120: 345–354.
Hardingham GE, Fukunaga Y, Bading H . Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat Neurosci 2002; 5: 405–414.
Lozovaya NA, Grebenyuk SE, Tsintsadze T, Feng B, Monaghan DT, Krishtal OA . Extrasynaptic NR2B and NR2D subunits of NMDA receptors shape 'superslow' afterburst EPSC in rat hippocampus. J Physiol 2004; 558: 451–463.
Tsvetkov E, Shin RM, Bolshakov VY . Glutamate uptake determines pathway specificity of long-term potentiation in the neural circuitry of fear conditioning. Neuron 2004; 41: 139–151.
Marcaggi P, Attwell D . Short- and long-term depression of rat cerebellar parallel fibre synaptic transmission mediated by synaptic crosstalk. J Physiol 2007; 578: 545–550.
Kullmann DM, Asztely F . Extrasynaptic glutamate spillover in the hippocampus: evidence and implications. Trends Neurosci 1998; 21: 8–14.
Murphy-Royal C, Dupuis JP, Varela JA, Panatier A, Pinson B, Baufreton J et al. Surface diffusion of astrocytic glutamate transporters shapes synaptic transmission. Nat Neurosci 2015; 18: 219–226.
Anticevic A, Cole MW, Repovs G, Murray JD, Brumbaugh MS, Winkler AM et al. Characterizing thalamo-cortical disturbances in schizophrenia and bipolar illness. Cereb Cortex 2014; 24: 3116–3130.
Fries P . Neuronal gamma-band synchronization as a fundamental process in cortical computation. Annu Rev Neurosci 2009; 32: 209–224.
Ribary U . Dynamics of thalamo-cortical network oscillations and human perception. Prog Brain Res 2005; 150: 127–142.
Roux F, Wibral M, Singer W, Aru J, Uhlhaas PJ . The phase of thalamic alpha activity modulates cortical gamma-band activity: evidence from resting-state MEG recordings. J Neurosci 2013; 33: 17827–17835.
Lisman J . Working memory: the importance of theta and gamma oscillations. Curr Biol 2010; 20: R490–R492.
Lisman J, Buzsaki G . A neural coding scheme formed by the combined function of gamma and theta oscillations. Schizophr Bull 2008; 34: 974–980.
Acknowledgements
This work was supported by MH53327 (JHM-W), MH88752 (JHM-W), MH094445 (REM), MH074016 (REM) and Doris Duke Clinical Scientist Award (REM). This work was also supported by the Lindsay Brinkmeyer Schizophrenia Research Fund.
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McCullumsmith, R., O’Donovan, S., Drummond, J. et al. Cell-specific abnormalities of glutamate transporters in schizophrenia: sick astrocytes and compensating relay neurons?. Mol Psychiatry 21, 823–830 (2016). https://doi.org/10.1038/mp.2015.148
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DOI: https://doi.org/10.1038/mp.2015.148
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