Title:
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Investigating the behavioural and molecular consequences of the loss of metabotropic glutamate receptor 2 in a Han Wistar rat strain
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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.
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