Gene expression of glutamate transporters SLC1A1, SLC1A3 and SLC1A6 in the cerebellar subregions of elderly schizophrenia patients and effects of antipsychotic treatment

Abstract

Objectives. The glutamatergic hypothesis of schizophrenia proposes alterations of excitatory amino acid transporters (solute carrier family, SLCs) expression and cerebellar dysfunctions. The influence of the neuregulin-1 (NRG1) risk genotype or effects of antipsychotics on expression of EAATs are unknown. Methods. We compared post-mortem samples from the cerebellar hemispheres and vermis of 10 schizophrenia patients with nine normal subjects by investigating gene expression of SLC1A3, SLC1A1 and SLC1A6 by in-situ hybridization. We further assessed the allelic composition regarding the polymorphism rs35753505 (SNP8NRG221533) near the NRG1 gene. To control for effects due to antipsychotic treatment, we chronically treated rats with the antipsychotics haloperidol or clozapine and assessed gene expression of SLCs. Results. Schizophrenia patients showed increased expression of SLC1A3 in the molecular layer of the vermis. Individuals carrying at least one C allele of rs35753505 (SNP8NRG221533) showed decreased expression of SLC1A6 in the molecular layer of both hemispheres, compared to individuals homozygous for the T allele. The animal model revealed suppression of SLC1A6 by clozapine. Conclusions. Increased SLC1A3 expression indicates facilitated transport and may result in reduced glutamate neurotransmission. Decreased SLC1A6 expression in NRG1 risk variant may be an adaptive effect to restore glutamate signalling, but treatment effects cannot be excluded.

Key words::

• Glutamate transporters
• gene expression
• cerebellum
• schizophrenia
• antipsychotics

Acknowledgement

This work was supported by the European Commission under the Sixth Framework Programme (BrainNet Europe II, LSHM-CT-2004-503039). The paper reflects only the authors’ views and the Community is not liable for any use that may be made of it. The authors would like to thank Udo Rueb for Braak staging and Mrs. Waltraud VanSyckel for her valuable assistance with language revision.

Statement of Interest

M. von Wilmsdorff, C. Blaich, J. Treutlein, M. Bauer, T. Schulze, T. Schneider-Axmann, M. Rietschel and A. Schmitt report no conflicts of interest. M. Zink received unrestricted scientific grants of Pfizer Pharma GmbH and Bristol Myers Squibb Pharmaceuticals; further speaker and travel grants were provided from AstraZeneca, Lilly, Pfizer Pharma GmbH, Bristol Myers Squibb Pharmaceuticals and Janssen Cilag. O. Gruber was honorary speaker for the following companies: AstraZeneca, Bristol Myers Squibb, Janssen Cilag, Lilly, Otsuka. O. Gruber has been invited to scientific congresses by Astra Zeneca, Janssen Cilag, Pfizer. P. Falkai was honorary speaker for Janssen-Cilag, AstraZeneca, Lilly, BMS, Lundbeck, Pfizer, Bayer Vital, SKB, Wyeth, Essex and during the last two years, but not presently, he was member of the advisory boards of Janssen-Cilag, AstraZeneca, Lilly and Lundbeck.