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Group III metabotropic glutamate receptors have attracted a great deal of interest due to their involvement in neuroinflammation – a component of diseases such as Alzheimer’s disease, Parkinson’s disease and multiple sclerosis. A critical step in neuroinflammation is damage to oligodendrocytes and glial cell activation within the central nervous system (CNS). Crosstalk between inflammatory responses and glutamatergic signaling links neuroinflammation with excitotoxicity.
Previous work demonstrated that the metabotropic glutamate receptor 4 (mGlu4) is capable of modulating the immune response in the peripheral nervous system. A new study looked at the CNS and showed that activation of astrocytic mGlu4 accelerates oligodendrocyte maturation and enhances oligodendrocyte survival following excitotoxic insult1. Treating oligodendrocytes with the mGlu4 agonist L-AP4 protected them from kainate-induced excitotoxicity, but only in the presence of astrocytes. The mGlu4 positive allosteric modulator (PAM) PHCCC mimicked this, while treatment with the mGlu4 antagonist CPPG inhibited this neuroprotective effect.
Transforming growth factor β (TGF-β) secreted from astrocytes, following stimulation of mGlu4, mediated the protective effects against excitotoxic insult. Compounds targeting mGlu4 on glial cells could therefore be effective in managing neuroinflammatory conditions.
Glutamatergic signaling through the metabotropic glutamate receptor 5 (mGlu5) is often associated with depression, yet there is little research around its role in stress – a precursor to depression.
Recently, mGlu5 has been shown to play a critical role in promoting resilience to chronic stress through the induction of the transcription factor ΔFoSB2 found within the nucleus accumbens (NAc). Using knockout mice (mGluR5−/−), researchers employed multiphasic stress-based models of depression as well as modified single-session tests to simulate chronic stress.
Mice lacking mGlu5 showed clear depression-like behaviors that were reduced following lentiviral rescue of mGlu5. mGluR5−/− mice also exhibited defective ΔFoSB induction, while pharmacological activation of mGlu5 with CDPPB upregulated ΔFoSB expression.
Activation of mGlu5 in the NAc and the induction of ΔFoSB are both necessary and sufficient to promote resistance to chronic stress in mice. This is the first evidence that mGlu5 mediates stress resilience. A stress-resilience-promoting receptor like mGlu5 holds obvious potential as a druggable target to prevent, rather than just treat, chronic depression.
Transient cerebral global ischemia, resulting from events such as cardiac arrest and hypovolemic shock, causes selective neurodegeneration in vulnerable regions of the brain. The metabotropic glutamate receptor 2 (mGlu2) is implicated in this neuronal vulnerability to ischemic damage.
Researchers recently highlighted that global ischemia epigenetically down-regulates mGlu2 expression in vulnerable neurons of the CA1 hippocampal region, but not in the CA3 region3. This down-regulation during the development of ischemic damage occasionally preceded neuronal death and could represent a neuroprotective mechanism to constrain neuronal damage. Levels of mGlu2 mRNA were much lower in CA3 regions than in CA1 regions, possibly contributing to that region’s resistance to ischemic damage.
Treatment with an mGlu2 PAM amplified neuronal damage in the CA1 region and caused neuronal death in CA3 region, while treatment with an mGlu2 negative allosteric modulator (NAM) was highly neuroprotective. These results suggest that mGlu2 NAMs may be useful in the treatment of cardiac arrest, hypovolemic shock, severe hypotension or other pathologies that damage vulnerable hippocampal neurons.
1. Spampinato, S. F., Merlo, S., Chisari, M., Nicoletti, F. & Sortino, M. A. Glial metabotropic glutamate receptor-4 increases maturation and survival of oligodendrocytes. Front. Cell. Neurosci. 8, 462 (2015).
2. Shin, S. et al. mGluR5 in the nucleus accumbens is critical for promoting resilience to chronic stress. Nat. Neurosci. 18, 1017–1024 (2015).
3. Motolese, M. et al. Targeting type-2 metabotropic glutamate receptors to protect vulnerable hippocampal neurons against ischemic damage. Mol. Brain 8, 66 (2015).