Neuroinflammation and dysregulation of glutamate in schizophrenia

Student thesis: Phd


Neuroinflammation and dysregulation of glutamate in schizophrenia A thesis submitted to the University of Manchester for the degree of Doctor of Philosophy in the Faculty of Biology, Medicine and Health by Catherine J Gregory, June 2019 Background: Schizophrenia is a mental illness with a lifetime prevalence of 7 in 1000 people. In some, symptoms can persist despite treatment with antipsychotic medication, leading to a poor quality of life. There has been a drive to better understand the pathophysiology behind schizophrenia, with the hope of developing more effective treatments. There is good evidence for a role of hypofunction of the glutamatergic N-methyl-D-aspartate receptor (NMDAR) in schizophrenia, as well as for a role of neuroinflammation. However, how these processes may vary across the illness duration and with antipsychotic exposure is unclear. In particular, how these processes may be linked is uncertain. There is emerging evidence that they may be linked via neuroinflammation-mediated activation of the kynurenine pathway of tryptophan degradation and the production of neuroactive metabolites such as the endogenous NMDAR antagonist kynurenic acid. However, no study to date has measured neuroinflammation and NMDAR hypofunction in the same patients. Methods: Patients with recent onset (n=20) and chronic (n=21) schizophrenia were recruited along with age- and sex-matched healthy controls (n=19). Positron emission tomography (PET) and the 18kDa translocator protein (TSPO) radioligand [11C]-(R)-PK11195 measured TSPO availability as an indication of microglial activation, a putative measure of neuroinflammation. 1H magnetic resonance spectroscopy (MRS) measured concentrations of glutamate, glutamine and gamma-aminobutyric acid (GABA) as an indication of NMDAR function, as well as myo-inositol, a putative glial marker. Results: In the first study of its kind, we found a positive correlation between TSPO availability and glutamate in antipsychotic-free patients with recent onset illness, which was not present in antipsychotic-exposed or chronic patients. We also found a reduction in TSPO availability in antipsychotic-free recent onset schizophrenia compared to controls but no difference in antipsychotic-exposed or chronic patients. We found no difference in glutamate, glutamine or GABA between recent onset or chronic schizophrenia and controls. We found a weak positive correlation between myo-inositol and TSPO availability in schizophrenia but no difference in myo-inositol concentration between patients and controls. Conclusions: Our results provide evidence for a link between TSPO availability and glutamate concentration in antipsychotic-free recent onset schizophrenia. This association appears to be moderated by antipsychotic medication. The lack of group differences in TSPO availability or glutamate suggest that significant neuroinflammation leading to glutamatergic dysfunction may only be present in a subset of schizophrenia, such as those with treatment resistance. Further investigation is needed in this cohort of patients. We also found preliminary evidence in support of a role for myo-inositol as a potential MR marker of microglia, but further confirmatory evidence is needed.
Date of Award31 Dec 2019
Original languageEnglish
Awarding Institution
  • The University of Manchester
SupervisorBill Deakin (Supervisor) & Peter Talbot (Supervisor)


  • schizophrenia
  • GABA
  • glutamate
  • positron emission tomography
  • neuroinflammation
  • magnetic resonance spectroscopy

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