A metabotropic glutamate receptor 3 (mGlu3R) isoform playing neurodegenerative roles in astrocytes is prematurely up-regulated in an Alzheimer's model

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 A beta neurotoxicity through stimulation of both neurotrophin release and A beta uptake. Alternative-spliced variants of mGlu3R were found in human brains. The most prevalent variant, mGlu3 Delta 4, 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 mGlu3 Delta 4 and Alzheimer's disease (AD) in the preclinical murine model PDAPP-J20, as well as a deleterious effect of mGlu3 Delta 4 in astrocytes. As assessed by western blot, hippocampal mGlu3R levels progressively decreased with age in PDAPP-J20 mice. On the contrary, mGlu3 Delta 4 levels were drastically increased with aging in nontransgenic mice, but prematurely overexpressed in 5-month-old PDAPP-J20-derived hippocampi, prior to massive senile plaque deposition. Also, we found that mGlu3 Delta 4 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 mGlu3 Delta 4, whose levels were reduced by A beta, thereby discouraging a causal effect of A beta on mGlu34 induction. However, heterologous expression of mGlu3 Delta 4 in astrocytes induced cell death, inhibited mGlu3R expression, and prevented mGlu3R-dependent A beta glial uptake. Indeed, mGlu3 Delta 4 promoted neurodegeneration in neuron-glia co-cultures. These results provide evidence of an inhibitory role of mGluadott in mGlu3R-mediated glial neuroprotective pathways, which may lie behind AD onset.