Hostname: page-component-848d4c4894-tn8tq Total loading time: 0 Render date: 2024-07-01T02:06:20.408Z Has data issue: false hasContentIssue false
  • English
  • Français

Effect of glutamate transporter EAAT2 gene variants and gray matter deficits on working memory in schizophrenia

Published online by Cambridge University Press:  15 April 2020

S. Poletti ,
D. Radaelli ,
M. Bosia ,
M. Buonocore ,
A. Pirovano ,
C. Lorenzi ,
R. Cavallaro ,
E. Smeraldi  and
F. Benedetti
S. Poletti*
Affiliation:
Department of Clinical Neurosciences, Scientific Institute and University Vita-Salute San Raffaele, Milan, Italy Centro di Eccellenza Risonanza Magnetica ad Alto Campo (CERMAC), University Vita-Salute San Raffaele, Milan, Italy
D. Radaelli
Affiliation:
Department of Clinical Neurosciences, Scientific Institute and University Vita-Salute San Raffaele, Milan, Italy Centro di Eccellenza Risonanza Magnetica ad Alto Campo (CERMAC), University Vita-Salute San Raffaele, Milan, Italy
M. Bosia
Affiliation:
Department of Clinical Neurosciences, Scientific Institute and University Vita-Salute San Raffaele, Milan, Italy
M. Buonocore
Affiliation:
Department of Clinical Neurosciences, Scientific Institute and University Vita-Salute San Raffaele, Milan, Italy
A. Pirovano
Affiliation:
Department of Clinical Neurosciences, Scientific Institute and University Vita-Salute San Raffaele, Milan, Italy
C. Lorenzi
Affiliation:
Department of Clinical Neurosciences, Scientific Institute and University Vita-Salute San Raffaele, Milan, Italy
R. Cavallaro
Affiliation:
Department of Clinical Neurosciences, Scientific Institute and University Vita-Salute San Raffaele, Milan, Italy
E. Smeraldi
Affiliation:
Department of Clinical Neurosciences, Scientific Institute and University Vita-Salute San Raffaele, Milan, Italy Centro di Eccellenza Risonanza Magnetica ad Alto Campo (CERMAC), University Vita-Salute San Raffaele, Milan, Italy
F. Benedetti
Affiliation:
Department of Clinical Neurosciences, Scientific Institute and University Vita-Salute San Raffaele, Milan, Italy Centro di Eccellenza Risonanza Magnetica ad Alto Campo (CERMAC), University Vita-Salute San Raffaele, Milan, Italy
*
*Corresponding author. Istituto Scientifico Ospedale San Raffaele, Department of Clinical Neurosciences, San Raffaele Turro, Via Stamira d’Ancona 20, Milano, Italy. Tel.: +39 02 26433156; fax: +39 02 26433265. E-mail address: poletti.sara@hsr.it (S. Poletti).
Get access

Abstract

Glutamate is the major excitatory neurotransmitter in the brain, with up to 40% of all synapses being glutamatergic. An altered glutamatergic transmission could play a critical role in working memory deficts observed in schizophrenia and could underline progressive changes such as grey matter loss throughout the brain. The aim of the study was to investigate if gray matter volume and working memory could be modulated by a genetic polymorphism related to glutamatergic function. Fifty schizophrenia patients underwent magnetic resonance and working memory testing outside of the scanner and were genotyped for rs4354668 EAAT2 polymorphism. Carriers of the G allele had lower gray matter volumes than T/T homozygote and worse working memory performance. Poor working memory performance was associated with gray matter reduction. Differences between the three genotypes are more relevant among patients showing poor performance at the 2-back task. Since glutamate abnormalities are known to be involved in excitotoxic processes, the decrease in cortical thickness observed in schizophrenia patients could be linked to an excess of extracellular glutamate. The differential effect of EAAT2 observed between good and poor performers suggests that the effect of EEAT2 on gray matter might reveal in the presence of a pathological process affecting gray matter.

Keywords

SchizophreniaEAAT2GlutamateWorking memoryStructural imaging
Type
Original articles
Information
European Psychiatry , Volume 29 , Issue 4 , May 2014 , pp. 219 - 225
Copyright
Copyright © European Psychiatric Association 2014

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Footnotes

Abbreviation: EAAT, Excitatory amino-acid transporter

References

Anselmetti, S., Poletti, S., Ermoli, E., Bechi, M., Cappa, S., Venneri, A.et al.The brief assessment of cognition in schizophrenia. Normative data for the Italian population. Neurol Sci 2008;29:85–92.CrossRefGoogle ScholarPubMed
Arnsten, A.F.Stress signalling pathways that impair prefrontal cortex structure and function. Nat Rev Neurosci 2009;10:410–422.CrossRefGoogle ScholarPubMed
Ashburner, J., Friston, K.J.Unified segmentation. Neuroimage 2005;26(3):839–851.CrossRefGoogle ScholarPubMed
Bauer, D., Haroutunian, V., Meador-Woodruff, J.H., McCullumsmith, R.E.Abnormal glycosylation of EAAT1 and EAAT2 in prefrontal cortex of elderly patients with schizophrenia. Schizophr Res 2010;117:92–98.CrossRefGoogle ScholarPubMed
Bliss, T.V., Collingridge, G.L.A synaptic model of memory: long-term potentiation in the hippocampus. Nature 1993;361:31–39.CrossRefGoogle ScholarPubMed
Bunch, L., Erichsen, M.N., Jensen, A.A.Excitatory amino acid transporters as potential drug targets. Expert Opin Ther Targets 2009;13:719–731.CrossRefGoogle ScholarPubMed
Callicott, J.H., Ramsey, N.F., Tallent, K., Bertolino, A., Knable, M.B., Coppola, R.et al.Functional magnetic resonance imaging brain mapping in psychiatry: methodological issues illustrated in a study of working memory in schizophrenia. Neuropsychopharmacology 1998;18:186–196.CrossRefGoogle Scholar
Chan, H., Butterworth, R.F.Evidence for an astrocytic glutamate transporter deficit in hepatic encephalopathy. Neurochem Res 1999;24:1397–1401.CrossRefGoogle ScholarPubMed
Danbolt, N.C.Glutamate uptake. Prog Neurobiol 2001;65:1–105.CrossRefGoogle ScholarPubMed
de Bartolomeis, A., Sarappa, C., Magara, S., Iasevoli, F.Targeting glutamate system for novel antipsychotic approaches: relevance for residual psychotic symptoms and treatment resistant schizophrenia. Eur J Pharmacol 2012;682:1–11.CrossRefGoogle ScholarPubMed
Deakin, J.F., Simpson, M.D.A two-process theory of schizophrenia: evidence from studies in post-mortem brain. J Psychiatr Res 1997;31:277–295.CrossRefGoogle ScholarPubMed
Egan, M.F., Straub, R.E., Goldberg, T.E., Yakub, I., Callicott, J.H., Hariri, A.R.et al.Variation in GRM3 affects cognition, prefrontal glutamate, and risk for schizophrenia. Proc Natl Acad Sci U S A 2004;101:12604–12609.CrossRefGoogle ScholarPubMed
Fairman, W.A., Amara, S.G.Functional diversity of excitatory amino acid transporters: ion channel and transport modes. Am J Physiol 1999;277:F481–F486.Google ScholarPubMed
Gaspar, P.A., Bustamante, M.L., Silva, H., Aboitiz, F.Molecular mechanisms underlying glutamatergic dysfunction in schizophrenia: therapeutic implications. J Neurochem 2009;111:891–900.CrossRefGoogle ScholarPubMed
Glahn, D.C., Ragland, J.D., Abramoff, A., Barrett, J., Laird, A.R., Bearden, C.E.et al.Beyond hypofrontality: a quantitative meta-analysis of functional neuroimaging studies of working memory in schizophrenia. Hum Brain Mapp 2005;25:60–69.CrossRefGoogle Scholar
Goldman-Rakic, P.S.Cellular basis of working memory. Neuron 1995;14:477–485.CrossRefGoogle ScholarPubMed
Good, C.D., Johnsrude, I.S., Ashburner, J., Henson, R.N., Friston, K.J., Frackowiak, R.S.A voxel-based morphometric study of ageing in 465 normal adult human brains. Neuroimage 2001;14(1 Pt 1):21–36.CrossRefGoogle ScholarPubMed
Harrison, P.J., Weinberger, D.R.Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry 2005;10:40–68 [Image 45].CrossRefGoogle ScholarPubMed
Hawkins, K.A., Addington, J., Keefe, R.S., Christensen, B., Perkins, D.O., Zipurksy, R.et al.Neuropsychological status of subjects at high risk for a first episode of psychosis. Schizophr Res 2004;67:115–122.CrossRefGoogle ScholarPubMed
Honea, R., Crow, T.J., Passingham, D., Mackay, C.E.Regional deficits in brain volume in schizophrenia: a meta-analysis of voxel-based morphometry studies. Am J Psychiatry 2005;162(12):2233–2245.CrossRefGoogle ScholarPubMed
Katagiri, H., Tanaka, K., Manabe, T.Requirement of appropriate glutamate concentrations in the synaptic cleft for hippocampal LTP induction. Eur J Neurosci 2001;14:547–553.CrossRefGoogle ScholarPubMed
Kim, K., Lee, S.G., Kegelman, T.P., Su, Z.Z., Das, S.K., Dash, R.et al.Role of excitatory amino acid transporter-2 (EAAT2) and glutamate in neurodegeneration: opportunities for developing novel therapeutics. J Cell Physiol 2011;226:2484–2493.CrossRefGoogle ScholarPubMed
Krystal, J.H., Karper, L.P., Seibyl, J.P., Freeman, G.K., Delaney, R., Bremner, J.D.et al.Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 1994;51:199–214.CrossRefGoogle ScholarPubMed
Krystal, J.H., D'Souza, D.C., Mathalon, D., Perry, E., Belger, A., Hoffman, R.NMDA receptor antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm shift in medication development. Psychopharmacology (Berl) 2003;169:215–233.CrossRefGoogle Scholar
Lauriat, T.L., Dracheva, S., Chin, B., Schmeidler, J., McInnes, L.A., Haroutunian, V.Quantitative analysis of glutamate transporter mRNA expression in prefrontal and primary visual cortex in normal and schizophrenic brain. Neuroscience 2006;137:843–851.CrossRefGoogle ScholarPubMed
Lencz, T., Smith, C.W., McLaughlin, D.M., Auther, A., Nakayama, E., Hovey, L.et al.Generalized and specific neurocognitive deficits in prodromal schizophrenia. Biological Psychiatry [in press].Google Scholar
Lewis, D.A., Gonzalez-Burgos, G.Pathophysiologically based treatment interventions in schizophrenia. Nat Med 2006;12:1016–1022.CrossRefGoogle Scholar
Li, S., Mallory, M., Alford, M., Tanaka, S., Masliah, E.Glutamate transporter alterations in Alzheimer disease are possibly associated with abnormal APP expression. J Neuropathol Exp Neurol 1997;56:901–911.CrossRefGoogle ScholarPubMed
Lisman, J.E., Coyle, J.T., Green, R.W., Javitt, D.C., Benes, F.M., Heckers, S.et al.Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia. Trends Neurosci 2008;31:234–242.CrossRefGoogle Scholar
Mallolas, J., Hurtado, O., Castellanos, M., Blanco, M., Sobrino, T., Serena, J.et al.A polymorphism in the EAAT2 promoter is associated with higher glutamate concentrations and higher frequency of progressing stroke. J Exp Med 2006;203:711–717.CrossRefGoogle ScholarPubMed
Martin, L.J., Brambrink, A.M., 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.CrossRefGoogle ScholarPubMed
Matute, C., Melone, M., Vallejo-Illarramendi, A., Conti, F.Increased expression of the astrocytic glutamate transporter GLT-1 in the prefrontal cortex of schizophrenics. Glia 2005;49:451–455.CrossRefGoogle ScholarPubMed
Meador-Woodruff, J.H., Healy, D.J.Glutamate receptor expression in schizophrenic brain. Brain Res Brain Res Rev 2000;31:288–294.CrossRefGoogle ScholarPubMed
Meyer, T., Ludolph, A.C., Morkel, M., Hagemeier, C., Speer, A.Genomic organization of the human excitatory amino acid transporter gene GLT-1. Neuroreport 1997;8:775–777.CrossRefGoogle ScholarPubMed
Moghaddam, B.Bringing order to the glutamate chaos in schizophrenia. Neuron 2003;40:881–884.CrossRefGoogle Scholar
Ohnuma, T., Augood, S.J., Arai, H., McKenna, P.J., Emson, P.C.Expression of the human excitatory amino acid transporter 2 and metabotropic glutamate receptors 3 and 5 in the prefrontal cortex from normal individuals and patients with schizophrenia. Brain Res Mol Brain Res 1998;56:207–217.CrossRefGoogle ScholarPubMed
Ohnuma, T., Tessler, S., Arai, H., Faull, R.L., McKenna, P.J., Emson, P.C.Gene expression of metabotropic glutamate receptor 5 and excitatory amino acid transporter 2 in the schizophrenic hippocampus. Brain Res Mol Brain Res 2000;85:24–31.CrossRefGoogle ScholarPubMed
Olney, J.W., Farber, N.B.Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry 1995;52:998–1007.CrossRefGoogle Scholar
Omdal, R., Brokstad, K., Waterloo, K., Koldingsnes, W., Jonsson, R., Mellgren, S.I.Neuropsychiatric disturbances in SLE are associated with antibodies against NMDA receptors. Eur J Neurol 2005;12:392–398.CrossRefGoogle ScholarPubMed
Rothstein, J.D., Van Kammen, M., Levey, A.I., Martin, L.J., Kuncl, R.W.Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann Neurol 1995;38:73–84.CrossRefGoogle ScholarPubMed
Rothstein, J.D., Dykes-Hoberg, M., Pardo, C.A., Bristol, L.A., Jin, L., Kuncl, R.W.et al.Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron 1996;16:675–686.CrossRefGoogle Scholar
Smith, R.E., Haroutunian, V., Davis, K.L., Meador-Woodruff, J.H.Vesicular glutamate transporter transcript expression in the thalamus in schizophrenia. Neuroreport 2001;12:2885–2887.CrossRefGoogle Scholar
Smith, R.E., Haroutunian, V., Davis, K.L., Meador-Woodruff, J.H.Expression of excitatory amino acid transporter transcripts in the thalamus of subjects with schizophrenia. Am J Psychiatry 2001;158:1393–1399.CrossRefGoogle ScholarPubMed
Umbricht, D., Schmid, L., Koller, R., Vollenweider, F.X., Hell, D., Javitt, D.C.Ketamine-induced deficits in auditory and visual context-dependent processing in healthy volunteers: implications for models of cognitive deficits in schizophrenia. Arch Gen Psychiatry 2000;57:1139–1147.CrossRefGoogle Scholar
Van Snellenberg, J.X., Torres, I.J., Thornton, A.E.Functional neuroimaging of working memory in schizophrenia: task performance as a moderating variable. Neuropsychology 2006;20:497–510.CrossRefGoogle ScholarPubMed
Weinberger, D.R., Berman, K.F., RF, Z.Physiological dysf unction of dorsolateral prefrontal cortex in schizophrenia. I. Regional cerebral blood flow (rCBF) evidence. Arch Gen Psychiatry 1986;43:114–125.CrossRefGoogle Scholar
Woods, S.W., Breier, A., Zipursky, R.B., Perkins, D.O., Addington, J., Miller, et al.Randomized trial of olanzapine versus placebo in the symptomatic acute treatment of the schizophrenic prodrome. Biol Psychiatry 2003;54:453–464.CrossRefGoogle ScholarPubMed
Submit a response

Comments

No Comments have been published for this article.