Related Experiment Video
Updated: Mar 31, 2026
Using Enzyme-based Biosensors to Measure Tonic and Phasic Glutamate in Alzheimer's Mouse Models
Published on: May 3, 2017
Targeting type-2 metabotropic glutamate receptors to protect vulnerable hippocampal neurons against ischemic damage
Marta Motolese1, Federica Mastroiacovo1, Milena Cannella1
1Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Neuromed, 86077, Pozzilli, Italy.
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.
Insights
Metabotropic glutamate 2 (mGlu2) receptors are downregulated in vulnerable brain regions after ischemic injury. Targeting mGlu2 receptors with negative allosteric modulators shows neuroprotective potential against ischemic damage.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Investigating the role of metabotropic glutamate (mGlu) receptors in neuronal vulnerability to ischemic damage.
- Utilizing the 4-vessel occlusion (4-VO) model of transient global ischemia in rats, which selectively affects hippocampal CA1 pyramidal neurons.
Purpose of the Study:
- To determine if mGlu receptor subtype expression changes in the vulnerable CA1 region during ischemic damage.
- To assess if targeting specific mGlu receptors post-ischemia can provide neuroprotection.
Main Methods:
- Employing the 4-VO rat model to induce transient global ischemia.
- Analyzing mGlu receptor subtype mRNA levels in hippocampal CA1 and CA3 regions.
- Administering selective mGlu2 receptor negative allosteric modulators (NAMs) and enhancers post-ischemia.
Main Results:
- 4-VO significantly reduced mGlu2 receptor transcripts in the CA1 region before neuronal death was evident.
- Downregulation of mGlu2 receptors correlated with reduced H3 histone acetylation at the Grm2 promoter.
- Post-ischemic treatment with an mGlu2 receptor NAM (ADX92639) was highly neuroprotective, while an enhancer (LY487379) exacerbated damage.
Conclusions:
- The mGlu2 receptor plays a critical role in regulating neuronal vulnerability to ischemic injury.
- mGlu2 receptor NAMs represent promising candidates for experimental treatments of conditions involving brain hypoperfusion, such as shock and cardiac arrest.
