A metabotropic glutamate receptor 3 (mGlu3R) isoform playing neurodegenerative roles in astrocytes is prematurely up‐regulated in an Alzheimerʼs model

Abstract

Subtype 3 metabotropic glutamate receptor (mGlu3R) displays a broad range of neuroprotective effects. We previously demonstrated that mGlu3R activation in astrocytes protects hippocampal neurons from Aβ neurotoxicity through stimulation of both neurotrophin release and Aβ uptake. Alternative‐spliced variants of mGlu3R were found in human brains. The most prevalent variant, mGlu3Δ4, lacks exon 4 encoding the transmembrane domain and can inhibit ligand binding to mGlu3R. To date, neither its role in neurodegenerative disorders nor its endogenous expression in CNS cells has been addressed. The present paper describes for the first time an association between altered hippocampal expression of mGlu3Δ4 and Alzheimer's disease (AD) in the preclinical murine model PDAPP‐J20, as well as a deleterious effect of mGlu3Δ4 in astrocytes. As assessed by western blot, hippocampal mGlu3R levels progressively decreased with age in PDAPP‐J20 mice. On the contrary, mGlu3Δ4 levels were drastically increased with aging in nontransgenic mice, but prematurely over‐expressed in 5‐month‐old PDAPP‐J20‐derived hippocampi, prior to massive senile plaque deposition. Also, we found that mGlu3Δ4 co‐precipitated with mGlu3R mainly in 5‐month‐old PDAPP‐J20 mice. We further showed by western blot that primary cultured astrocytes and neurons expressed mGlu3Δ4, whose levels were reduced by Aβ, thereby discouraging a causal effect of Aβ on mGlu3Δ4 induction. However, heterologous expression of mGlu3Δ4 in astrocytes induced cell death, inhibited mGlu3R expression, and prevented mGlu3R‐dependent Aβ glial uptake. Indeed, mGlu3Δ4 promoted neurodegeneration in neuron–glia co‐cultures. These results provide evidence of an inhibitory role of mGlu3Δ4 in mGlu3R‐mediated glial neuroprotective pathways, which may lie behind AD onset.

Phosphorylation and regulation of group II metabotropic glutamate receptors (mGlu2/3) in neurons

“…These long-term changes may contribute to the remodeling of excitatory synaptic transmission and plasticity critical for the pathogenesis and symptomatology of chronic brain disorders. In fact, mGlu2/3 receptors have been linked to anxiety, schizophrenia, depression, chronic pain, drug addiction, and neurodegenerative disorders ( Nicoletti et al, 2011 ; Planas-Fontanez et al, 2020 ; Abd-Elrahman et al, 2021 ; Li et al, 2022 ; Mazzo et al, 2022 ; Turati et al, 2022 ). Emerging evidence shows that the serine phosphorylation state of mGlu2/3 monomers was elevated in the rat nucleus accumbens and prefrontal cortex following repeated administration of cocaine ( Xi et al, 2002 ).…”