Rabbit Anti-Mglur2 monoclonal antibody, clone KK102-10

Background: To examine whether metabotropic glutamate (mGlu) receptors have any role in mechanisms that shape neuronal vulnerability to ischemic damage, we used the 4-vessel occlusion (4-VO) model of transient global ischemia in rats. 4-VO in rats causes a selective death of pyramidal neurons in the hippocampal CA1 region, leaving neurons of the CA3 region relatively spared. We wondered whether changes in the expression of individual mGlu receptor subtypes selectively occur in the vulnerable CA1 region during the development of ischemic damage, and whether post-ischemic treatment with drugs targeting the selected receptor(s) affords neuroprotection. Results: We found that 4-VO caused significantly reduction in the transcript of mGlu2 receptors in the CA1 region at times that preceded the anatomical evidence of neuronal death. Down-regulation of mGlu2 receptors was associated with reduced H3 histone acetylation at the Grm2 promoter. The transcripts of other mGlu receptor subtypes were unchanged in the CA1 region of 4-VO rats. Ischemia did not cause changes in mGlu2 receptor mRNA levels in the resistant CA3 region, which, interestingly, were lower than in the CA1 region. Targeting the mGlu2 receptors with selective pharmacologic ligands had profound effects on ishemic neuronal damage. Post-ischemic oral treatment with the selective mGlu2 receptor NAM (negative allosteric modulator), ADX92639 (30 mg/kg), was highly protective against ischemic neuronal death. In contrast, s.c. administration of the mGlu2 receptor enhancer, LY487379 (30 mg/kg), amplified neuronal damage in the CA1 region and extended the damage to the CA3 region. Conclusion: These findings suggest that the mGlu2 receptor is an important player in mechanisms regulating neuronal vulnerability to ischemic damage, and that mGlu2 receptor NAMs are potential candidates in the experimental treatments of disorders characterized by brain hypoperfusion, such as hypovolemic shock and cardiac arrest.

Stress is a leading risk factor for the onset and recurrence of major depression. Enhancing stress resilience may be a therapeutic strategy to prevent the development of depression in at-risk populations or its recurrence in depressed patients. Group II metabotropic glutamate receptor (mGlu(2/3)) antagonists have been recognized for antidepressant-like actions in preclinical models, but have not been evaluated for prophylactic effects. We assessed the role of mGlu(2/3) in modulating stress resilience using subtype-specific knockout mice lacking mGlu(2) (Grm2(-/-)) or mGlu(3) (Grm3(-/-)), and pharmacological manipulations of mGlu(2/3) activity during or prior to the induction and reinstatement of stress-induced behavioral deficits. Grm2(-/-), but not Grm3(-/-), mice exhibited reduced forced-swimming test immobility time and were resilient to developing inescapable shock (IES)-induced escape deficits. Grm2(-/-) mice were also resilient to developing corticosterone (CORT)-induced escape deficits and chronic social defeat stress-induced anhedonia. Pharmacological blockade of mGlu(2/3) with the antagonist LY341495 during stress prevented the development of IES- and CORT-induced escape deficits, while activation with the agonist LY379268 increased susceptibility to escape deficits. Prophylactic treatment with the LY341495, both systemically and via microinjection into the medial prefrontal cortex (mPFC), up to 7 days before IES, prevented both the induction of escape deficits and their reinstatement by brief re-exposure to IES up to 20 days after treatment. Overall, blockade of mGlu(2/3) enhanced stress resilience and deletion of mGlu(2), but not mGlu(3), conferred a stress-resilient phenotype, indicating that prophylactic treatments reducing mGlu(2) activity may protect against stress-induced changes underlying the development or recurrence of stress-induced disorders, including depression.