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Title: Glutamate transporters in schizophrenia - post-mortem study and animal models
Author: Piyabhan, Pritsana
ISNI:       0000 0001 3492 308X
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2008
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There are several observations implicating abnormalities of glutamate in the brain in schizophrenia. Excitatory amino acid transporters (EAATs) and vesicular glutamate transporters (VGLUTs) have been suggested as valuable markers of glutamatergic innervation in brain tissue. My studies initially investigate EAAT3 and VGLUTl in hippocampus, and VGLUTl in other subc:ortical regions taken post-mortem from patients with schizophrenia, and affective disorders and control subjects, using immunohistochemistry and western blotting. An increased EAAT3-like immunoreactivity (LI) was observed in hippocampal CA2 of psychotic patients, suggesting an up-regulation reflecting glutamatergic hypofunction in this brain region associated with psychotic illness. A VGLUTl-LI deficit was observed in cauda~e in schizophrenia and in nucleus accumbens in depression. VGLUTl-LI deficits were also found in CA4 and dentate gyrus in, schizophrenia and bipolar disorder; providing evidence for diminished glutamatergic innervation in striatum and hippocampus in these disorders. Antipsychotic drug administration to rats had no effect on VGLUTl-LI, indicating that the deficit in' schizophrenia is unlikely to be a consequence of pharmacotherapy and thus likely to relate to disease pathology. VGLUTl-LI was also investigated in the prefrontal cortex, temporal cortex, striatum and hippocampus of schizophrenic animal models: social isolation and subchronic phencyclidine (PCP) administration in rats and in mice heterozygous for neuregulinl .eNRGI), a schizophrenic susceptibility gene. A VGLUTl-LI deficit was found in the prefrontal cortex and h'ippocampus after social isolation as seen in schizophrenia. VGLUTI-LI was increased in the prefrontal cortex and hippocampus after PCP administration in rats, suggesting disinhibition of GABAergic neurons enhancing glutamatergic innervation in this model. There were no VGLUTl abnormalities in NRGI-mutant mice. The at-risk genotypes of two NRGI polymorphisms were found to be associated with VGLUTl-LI deficits in human striatum and hippocampus, suggesting that these glutamatergic deficits may, in part, be genetically determined.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available