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Title: Exploration of the molecular mechanisms of cognitive dysfunction in schizophrenia using the sub-chronic PCP rodent model
Author: Glasper, James Edward
ISNI:       0000 0004 5356 300X
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2015
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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 (σ1) 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 σ1 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 α5-subunit mRNA and a decrease in α3 and δ subunit mRNA levels. No differences were observed in the mRNA levels of the other studied GABAA receptor subunits (α1, α2, α4 or γ2). No alterations in benzodiazepine site- or α5-subunit-containing GABAA receptors were seen following a 7-day washout period, although increased frontal cortical levels of α5-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 α5- and δ-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 σ1receptor agonist (PRE-084) at 1 and 3mg/kg and by the σ1receptor 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 σ1 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 σ1 receptor is a potential therapeutic target for recognition memory deficits in schizophrenia, as well as other disorders.
Supervisor: Not available Sponsor: b-neuro ; Janssen Pharmaceutica
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Rodent ; Phencyclidine ; Cognition ; GABA ; Sigma-1 receptor