Exploration of the molecular mechanisms of cognitive dysfunction in schizophrenia using the sub-chronic PCP rodent model

  • James Glasper

Student thesis: Phd


Cognitive dysfunction is a core symptom of schizophrenia, which is poorly treated by current antipsychotic medication. Deficits in the GABAergic system, as demonstrated by convergent genetic and [125I]-iomazenil imaging evidence from patients, are thought to underlie these cognitive deficits. The sub-chronic PCP rodent model was used as it shows cognitive and behavioural parallels to schizophrenia and therefore provides a translational model for some aspects of the disease. However the neurobiological mechanisms responsible for the behavioural alterations in this model have not been fully elucidated. The main aim of the studies presented in this thesis was to investigate the construct validity of the sub-chronic PCP model in relation to the GABAergic and sigma-1 (sigma1) receptor systems. Transcriptional changes in gene markers were studied using qRT-PCR and proteomic alterations were investigated using radioligand binding, autoradiography and Western blotting. Finally, the cognitive enhancing potential of sigma1 receptor modulators was tested using the novel object recognition (NOR) task.Data presented in chapter 3 shows that sub-chronic PCP treatment in rats produces an increase in GABAA receptor alpha5-subunit mRNA and a decrease in alpha3 and delta subunit mRNA levels. No differences were observed in the mRNA levels of the other studied GABAA receptor subunits (alpha1, alpha2, alpha4 or γ2). No alterations in benzodiazepine site- or alpha5-subunit-containing GABAA receptors were seen following a 7-day washout period, although increased frontal cortical levels of alpha5-subunit protein were observed prior to the washout period. This suggests that sub-chronic PCP treatment affects extrasynaptic cortical GABAA receptor expression, as shown by the alterations in alpha5- and delta-subunits, which may contribute to the cognitive deficits observed in this model.Studies in chapter 4 showed that sub-chronic PCP administration causes frontal cortical reductions in parvalbumin, GAD67, GABA transporter-1 and calretinin mRNA levels. No alterations were observed for somatostatin, GAD65, or GABA transporter-3 mRNA, although changes in the mRNA levels for the astrocytic marker glial fibrillary acidic protein were observed in the cerebellum, frontal cortex and hippocampus of sub-chronic PCP-treated animals. No differences in the frontal cortical protein levels of GAD67, GAT-1 and calretinin were observed, suggesting that any proteomic differences in these markers which are present in the sub-chronic PCP model, they are limited in a layer- or cell-type-specific manner. The NOR task is a translational cognitive test that measures recognition memory, which is known to be impaired in schizophrenia. Data in chapter 5 of this thesis showed that sub-chronic PCP-induced and delay-induced recognition memory deficits were ameliorated by acute administration of the sigma1receptor agonist (PRE-084) at 1 and 3mg/kg and by the sigma1receptor antagonist (NE-100) at 1mg/kg. NE-100 at 3mg/kg proved effective at ameliorating delay-, but not PCP-induced memory deficits. No procognitive effect was observed at lower concentrations of either compound or by co-administration of both compounds. These observations suggest that the improvement of recognition memory deficits is mediated, in part, by sigma1 receptors in female rats. The overall results of these studies suggest that sub-chronic PCP administration causes frontal cortical transcriptional alterations in GABAergic neuronal markers which correlate to clinical findings in schizophrenia patients, although these alterations were not observed at the proteomic level following the washout period. These findings also suggest that the sigma1 receptor is a potential therapeutic target for recognition memory deficits in schizophrenia, as well as other disorders.
Date of Award1 Aug 2015
Original languageEnglish
Awarding Institution
  • The University of Manchester
SupervisorJoanna Neill (Supervisor) & Michael Harte (Supervisor)


  • GABA
  • Cognition
  • Sigma-1 receptor
  • Rodent
  • Phencyclidine

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