Chen, Andrew Chih-Hui; (1997) The glutamate receptor genes and schizophrenia: Gene expression studies of antipsychotic drug action and linkage analysis of the genetic susceptibility. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Schizophrenia is a severe disabling neuropsychiatric syndrome affecting 0.85% of most human populations. Family, twin, and adoption studies in several ethnic populations have consistently implicated genetic factors as having an important pathogenic role in the disease. However, researchers have only recently begun to detect consistent evidence of linkage between schizophrenia and genetic markers, but no candidate genes have yet been implicated. It has been hypothesized that glutamate receptor function is important in either the aetiology or treatment of schizophrenia and therefore the glutamate receptor family of genes are potential susceptibility loci for schizophrenia. To test this hypothesis, twenty-three English and Icelandic schizophrenia families containing multiple cases of schizophrenia were genotyped with currently available microsatellite polymorphisms localized at the GluR5, GluR6 glutamate receptors and SLC1A5 glutamate/aspartate transporter loci. Lod scores, model-free linkage analysis, and extended relative pair analysis methods were used to test for linkage. No evidence of close linkage between schizophrenia and any of these loci was found. In addition, in order to understand how specific glutamate receptor genes are involved in the treatment of schizophrenia, a multiprobe oligonucleotide solution hybridization (MOSH) technique was used to examine the regulation of gene expression of the ionotropic glutamate receptor subunit genes. Four regions of the left rat brain following treatment with the optical isomers of flupenthixol at a dose of 0.2 mg/kg/day over a period of 1, 2, 4, 8, 12, 24 weeks were studied. A previous controlled trial showed that cis-flupenthixol had a significantly superior ability to ameliorate the positive symptoms of schizophrenia compared to its transisomer. Protein levels of the NMD A receptor subunit NR1, GluR2/3 and GluR6/7 glutamate receptors in the right brain were also examined by Western blotting technique with specific antibodies for these receptor subunits. In summary, the gene expression of specific NMD A receptor subunits in several regions of the left rat brain was altered by treatment with either the cis- or transisomer of the antipsychotic drug flupenthixol. NRl mRNA was significantly decreased throughout the 24 weeks treatment with trans-flupenthixol and after long-term (12 or 24 week) treatment with cis-flupenthixol in the frontal and subcortical areas. NR2B and NR2C mRNA expression demonstrated a dynamic pattern of change in different brain regions following treatment with flupenthixol whilst NR2A and NR2D gene expression was relatively unaffected except in the subcortical region. The gene expression of AMPA (GluRl-4) and kainate (GluR5-7, KA1, KA2) types of glutamate receptor subunits was unaffected following 4 and 24 weeks of treatment with either trans- or cis-flupenthixol. It would be difficult to make inferences about the pathophysiology of schizophrenia or any other psychiatric disorders solely based on drug mechanisms. However, these results indicate that adaptations in glutamate receptors may represent an important and novel mechanism through which neuroleptics exert some of their effects on brain function.

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