Involvement of the brain metabotropic glutamate receptor ^subtypes 5 and 7 in chronic psychosocial stress

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The role of the brain metabotropic glutamate receptor (mGluR) subtypes mGluR5 and mGluR7 in anxiety- and acute stress-related behaviours and physiology in rodents is well established, tn contrast, virtually nothing is known about their involvement in chronic stress. Here we intend to determine the effects of genetic ablation and local knock-down, as well as pharmacological modulation of mGluRS and mGtuR7 on behavioural and physiological consequences of chronic psychosocial stress in mice using the established chronic subordinate colony housing (CSC) paradigm. Also, we want to assess more broadly the effects of CSC on the mGluR system of the brain. Thus, quantitative PCR will be used to determine CSC-induced changes of mGluRl-8 and their intracellular regulatory proteins. Further, groups of knock-out mice of mGluRS, of mGluR7, and corresponding wild-types exposed to CSC will be assessed with respect to selected stress-related behavioural parameters, neuronal and hormonal HPA-axis responsiveness, selected brain mRNA levels, as well as immune functions. Moreover, selective pharmacological agents for mGluRS and mGtuR7 will be utilized to investigate their effects on the consequences of CSC and for comparison with the genetic knock-outs. Finally, local siRNA-mediated knock-down and overexpression of mGluRs, mediated by adeno-associated viral vectors, wilt further define the criticat involvement of the receptors in specific brain regions and will assist to dissect and suggest which mode and direction of mGluR subtype-modulation could be most beneficial for future therapeutic intervention in human disorders related to chronic psychosocial stress.