Cell-specific abnormalities of glutamate transporters in schizophrenia: sick astrocytes and compensating relay neurons?

• Published in: Molecular psychiatry 2016-06, Vol.21 (6), p.823-830
• Main Authors: McCullumsmith, R E, O’Donovan, S M, Drummond, J B, Benesh, F S, Simmons, M, Roberts, R, Lauriat, T, Haroutunian, V, Meador-Woodruff, J H
• Format: Article
• Language: English
• Subjects: 14/63; 631/378; 692/699/476/1799; 82/51; 82/80; Acids; Aged; Alternative splicing; Amino Acid Transport System X-AG - metabolism; Animals; Antipsychotics; Astrocytes; Astrocytes - metabolism; Behavioral Sciences; Biological Psychology; Biological transport; Brain; Carrier Proteins - genetics; Development and progression; Excitatory amino acid transporters; Experiments; Female; Gene Expression; Genetic aspects; Glutamate; Glutamate Plasma Membrane Transport Proteins - metabolism; Glutamic Acid - metabolism; Glutamic acid transporter; Health aspects; Humans; Hypotheses; Immunofluorescence; Localization; Male; Medicine; Medicine & Public Health; Mediodorsal Thalamic Nucleus - metabolism; Mediodorsal Thalamic Nucleus - physiopathology; Mental disorders; Mice; Middle Aged; Neurons; Neurons - metabolism; Neurosciences; original-article; Pharmacotherapy; Polymerase chain reaction; Properties; Protein expression; Protein transport; Proteins; Psychiatry; Psychotropic drugs; RNA, Messenger - metabolism; Schizophrenia; Schizophrenia - genetics; Schizophrenia - metabolism; Synapses; Thalamus; Thalamus - physiopathology
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/mp.2015.148

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.