The intricate role of metabotropic glutamate receptors, specifically mGlu2 and mGlu3 subtypes, has captured the attention of neuroscientists aiming to unravel new therapeutic avenues for Parkinson’s disease (PD). Initial research efforts were hampered by the use of orthosteric agonists, such as LY379268, which stimulate both mGlu2 and mGlu3 receptors indiscriminately, complicating the understanding of their distinct functions in neurodegeneration and neuroprotection within the basal ganglia motor circuits. This issue presented a significant challenge, as these receptors, despite structural similarities, diverge substantially in their role in neuroinflammation and synaptic modulation.
Groundbreaking work utilizing knockout mice selectively lacking either mGlu2 or mGlu3 receptors illuminated the unique role of mGlu2 receptors in mediating long-term depression (LTD) at the subthalamic nucleus (STN) to substantia nigra pars reticulata (SNpr) synapses. This synaptic plasticity is a core feature in basal ganglia function, and understanding its modulation by mGlu2 has profound implications for PD symptomatology, particularly motor control, where aberrant synaptic activity contributes to the disease’s hallmark motor deficits.
Pharmacological intervention with LY379268 has exhibited neuroprotective effects in standard Parkinsonian models such as 6-hydroxydopamine (6-OH-DA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). These studies demonstrated the compound’s ability to reduce akinesia symptoms in reserpine-treated animals, suggesting modulation of glutamatergic transmission through these receptors might be a viable strategy for slowing neurodegeneration. However, the inability to distinguish between mGlu2 and mGlu3 receptors inevitably blurred the mechanistic insight necessary for targeted therapeutic development.
Both mGlu2 and mGlu3 receptors share the property of inhibiting neurotransmitter release from presynaptic terminals, thus controlling excitotoxicity. Nonetheless, their differential expression patterns in glial cells mark a profound divergence in their implications for neuroinflammation and neuronal survival. Of particular note, mGlu3 receptors are uniquely expressed on astrocytes, where their activation induces the secretion of neurotrophic factors such as transforming growth factor-beta (TGF-β) and glial cell line-derived neurotrophic factor (GDNF). These factors are enormously influential in supporting neuronal health, combating excitotoxic damage, and promoting recovery of dopaminergic neurons, which are critically affected in PD.
Activation of mGlu3 receptors on astrocytes fosters a robust neuroprotective response, as shown in cultured neuronal-astrocyte systems where excitotoxic cell death is mitigated. This protective effect hinges upon the upregulation of GDNF, a neurotrophic factor renowned for its ability to stimulate survival and axonal regeneration of mesencephalic dopaminergic neurons. GDNF’s powerful neurorestorative traits have been substantiated across animal models, including rodents and non-human primates, highlighting its potential for clinical translation.
Intriguingly, the neuroprotective mechanism involving GDNF may be mediated through TGF-β signaling pathways, suggesting that mGlu3 receptor activation orchestrates a synergistic release of neurotrophic factors, ultimately enhancing neuronal resilience. This insight aligns with ongoing clinical efforts to deliver GDNF directly to affected brain regions, such as the putamen, using viral vectors like adeno-associated virus (AAV2). Encouragingly, early-phase trials have demonstrated the safety and tolerability of this gene therapy approach in advanced PD patients, with phase 2 studies currently underway to evaluate efficacy and biodistribution.
In contrast to mGlu3, selective mGlu2 activation has revealed neurotoxic effects in vitro and in animal models subjected to MPTP, emphasizing the necessity to carefully discern receptor subtype roles when developing pharmacotherapies. These divergent outcomes underscore a complex receptor-mediated dichotomy in glutamate signaling pathways influencing neuronal fate, synaptic dynamics, and disease progression.
Beyond astrocytes, mGlu3 receptors are also found on microglia, where their activation plays an anti-inflammatory role by promoting a shift towards a neuroprotective phenotypic profile. Neuroinflammatory insults, such as those induced by perinatal insults combining gestational low-protein diets and interleukin-1β administration, have been shown to downregulate microglial mGlu3 receptor expression, exacerbating inflammatory processes detrimental to brain development.
Experimental data demonstrate that either genetic deletion or pharmacological inhibition of microglial mGlu3 receptors recapitulates the pro-inflammatory state induced by perinatal inflammatory challenges. This finding indicates a critical endogenous role for mGlu3 receptors in restraining neuroinflammation through modulation of microglial activity, which is intimately linked to neurodegenerative disease progression, including PD.
Further reinforcing this concept, studies in mGlu3 receptor knockout mice subjected to MPTP intoxication reveal heightened vulnerability of nigrostriatal dopaminergic neurons. These animals exhibit amplified microglial activation in the substantia nigra pars compacta (SNpc) and reduced expression of anti-inflammatory cytokine genes in the striatum, reinforcing the protective role of mGlu3 signaling in microglial cells.
Genetic analyses have provided additional layers of evidence implicating the GRM3 gene, which encodes the mGlu3 receptor, in PD susceptibility. Distinct GRM3 haplotypes have been associated with both motor and non-motor symptoms of the disease. Furthermore, patients harboring specific PD-linked GRM3 variants demonstrate impaired cortical plasticity, as assessed by advanced neurophysiological techniques like magnetic transcranial stimulation, underscoring the receptor’s influence on central nervous system adaptability and dysfunction.
Taken together, the cumulative scientific evidence positions mGlu3 receptors at the crossroads of neuroprotection and neuroinflammation modulation, representing a promising target for disease-modifying interventions in PD. The development of selective positive allosteric modulators (PAMs) for mGlu3 receptors offers a tailored approach to amplify beneficial receptor signaling without the off-target effects associated with orthosteric agonists.
Such therapeutic agents are anticipated not only to mitigate neuroinflammatory cascades via microglial regulation but also to enhance astrocyte-mediated neurotrophic support, thus stalling or even reversing the progression of nigrostriatal degeneration. This dual action highlights a sophisticated mechanism of neurorestoration that may transform the clinical landscape of Parkinson’s disease management.
Future research focused on elucidating the precise intracellular signaling pathways activated by mGlu3 receptors in glial populations will be critical to optimize PAM development. Moreover, longitudinal clinical trials will be essential to establish the long-term efficacy and safety profiles of these novel compounds in PD patients, alongside biomarker-driven assessment of neuroinflammation and synaptic integrity.
In summary, the dichotomous functions of mGlu2 and mGlu3 receptors in the basal ganglia underscore the complexity of glutamatergic modulation in Parkinson’s disease. While mGlu2 receptors appear linked to adverse neuronal outcomes upon selective activation, mGlu3 receptors emerge as potent mediators of neuroprotection through coordinated glial responses. Harnessing the therapeutic potential of mGlu3-specific modulation may herald a new era in PD treatment, offering symptomatic relief combined with disease-modifying effects that address the underlying pathophysiology.
The convergence of genetic, pharmacological, and translational research reinforces the urgency to deepen our understanding of these receptor systems. This will ultimately facilitate the creation of precision medicine strategies capable of arresting neuronal loss, restoring motor function, and improving quality of life for millions affected by Parkinson’s disease worldwide.
Subject of Research: The distinct roles of metabotropic glutamate receptor subtypes mGlu2 and mGlu3 in neurodegeneration, neuroprotection, and neuroinflammation within Parkinson’s disease models.
Article Title: Targeting metabotropic glutamate receptors for symptomatic and disease-modifying treatment in Parkinson’s disease.
Article References:
Alborghetti, M., Ceccherelli, A., Caridi, M. et al. Targeting metabotropic glutamate receptors for symptomatic and disease-modifying treatment in Parkinson’s disease. npj Parkinsons Dis. 11, 290 (2025). https://doi.org/10.1038/s41531-025-01138-1
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