The Density of Group I mGlu5 Receptors Is Reduced along the Neuronal Surface of Hippocampal Cells in a Mouse Model of Alzheimer's Disease

Metabotropic glutamate receptor subtype 5 (mGlu(5)) is implicated in the pathophysiology of Alzheimer's disease (AD). However, its alteration at the subcellular level in neurons is still unexplored. Here, we provide a quantitative description on the expression and localisation patterns of mGlu(5) in the APP/PS1 model of AD at 12 months of age, combining immunoblots, histoblots and high-resolution immunoelectron microscopic approaches. Immunoblots revealed that the total amount of mGlu(5) protein in the hippocampus, in addition to downstream molecules, i.e., G(q/11) and PLC beta(1), was similar in both APP/PS1 mice and age-matched wild type mice. Histoblots revealed that mGlu(5) expression in the brain and its laminar expression in the hippocampus was also unaltered. However, the ultrastructural techniques of SDS-FRL and pre-embedding immunogold demonstrated that the subcellular localisation of mGlu(5) was significantly reduced along the neuronal surface of hippocampal principal cells, including CA1 pyramidal cells and DG granule cells, in APP/PS1 mice at 12 months of age. The decrease in the surface localisation of mGlu(5) was accompanied by an increase in its frequency at intracellular sites in the two neuronal populations. Together, these data demonstrate, for the first time, a loss of mGlu(5) at the plasma membrane and accumulation at intracellular sites in different principal cells of the hippocampus in APP/PS1 mice, suggesting an alteration of the excitability and synaptic transmission that could contribute to the cognitive dysfunctions in this AD animal model. Further studies are required to elucidate the specificity of mGlu(5)-associated molecules and downstream signalling pathways in the progression of the pathology.

Automated summary

In this study, alterations in the subcellular localization of mGlu(5) in neurons of APP/PS1 mice at 12 months of age were observed, with a significant reduction in surface localization and an increase in intracellular sites. This suggests a potential link to cognitive dysfunctions in this AD animal model and raises the need for further investigation into the specificity of mGlu(5)-associated molecules and downstream signaling pathways in disease progression.