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Title: Investigating the behavioural and molecular consequences of the loss of metabotropic glutamate receptor 2 in a Han Wistar rat strain
Author: Wood, Christian Michael
ISNI:       0000 0004 6056 8781
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2015
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Metabotropic glutamate receptor 2 (mGluR2) has been implicated in numerous physiological functions and pathological states. Recent work identified a Han Wistar rat strain that does not express mGluR2 and displays anxiety-like behaviours (Ceolin et al., 2011). Recent in-house data in HSD Han Wistar rats show the receptor loss is due to a nonsense mutation within the GRM2 gene. Initial studies in this thesis analysed the prevalence of this mutation in rat strains with the mutation observed in strains of Han Wistar and Wistar origin. Characterization of the physiological, behavioural and molecular consequences of the loss of mGluR2 was conducted in the HSD Han Wistar rats. Behavioural data indicated normal physiological and cognitive functioning in these rats, with encephalography work indicating normal sleep-wake architecture. Specific behavioural effects were observed in these rats with data showing an anxiety-like phenotype and increased ethanol preference. Observation of increased ethanol preference is consistent in rats lacking mGluR2 expression, whilst conflicting data exist on the effects of mGluR2 loss and the anxiety-like phenotype. Studies performed with mGluR2/3 agonists, antagonists and a 5HT2A/C agonist 2,5- Dimethoxy-4-iodoamphetamine (DOl) revealed distinct pharmacological changes in the mutant animals. The reversal of psychotomimetic-induced locomotor activity by an mGluR2/3 agonist was lost supporting a role for mGluR2 in these effects. Attenuated effects of the 5HTzA/c agonist DOl on behaviour and cortical oscillatory activity were also observed; consistent with a role of mGluR2 in 5HT2A mediated effects. NMDA receptor antagonist treatment induced varied effects in these rats, with an attenuation of a ketamine-induced deficit in cognitive performance, but a potentiated effect on cortical high-frequency oscillatory activity. These data suggest that glutamatergic challenges are significantly altered in rats lacking mGluR2 expression. However, these effects were paradigm specific, with a normal phencyclidine-induced locomotor response observed. Transcriptional analysis of the HSD Han Wistar rats by RNA sequencing indicated a similar expression profile in the two rat strains, with individual neurotransmission genes highlighted. Comparison with another mGluR2-lacking strain indicated genes that may be differentially expressed due to mGluR2 loss. These studies add to growing literature suggesting mGluR2 plays a key role in ethanol preference and mediate the antipsychotic effects of mGluR2/3 agonists. The work also suggests that mGluR2 expression is important in the 5HT2A receptor functional response. Further studies in these mutant rats are needed to understand the neurochemical effects associated with mGluR2 loss. These rats also provide a valuable model for future studies into mGluR2 function and transcriptional changes associated with receptor loss and behaviours such as ethanol preference.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available