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Abstract Glutamate receptors, including mGluR5, are involved in learning and memory impairments triggered by aging and neurological diseases. However, each condition involves distinct molecular mechanisms. It is still unclear whether the mGluR5 cell signaling pathways involved in normal brain aging differ from those altered due to neurodegenerative disorders. Here, we employed wild type (WT), mGluR5−/−, BACHD, which is a mouse model of Huntington’s Disease (HD), and mGluR5−/−/BACHD mice, at the ages of 2, 6 and 12 months, to distinguish the mGluR5-dependent cell signaling pathways involved in aging and neurodegenerative diseases. We demonstrated that the memory impairment exhibited by mGluR5−/− mice is accompanied by massive neuronal loss and decreased dendritic spine density in the hippocampus, similarly to BACHD and BACHD/mGluR5−/− mice. Moreover, mGluR5 ablation worsens some of the HD-related alterations. We also show that mGluR5−/− and BACHD/mGluR5−/− mice have decreased levels of PSD95, BDNF, and Arc/Arg3.1, whereas BACHD mice are mostly spared. PSD95 expression was affected exclusively by mGluR5 ablation in the aging context, making it a potential target to treat age-related alterations. Taken together, we reaffirm the relevance of mGluR5 for memory and distinguish the mGluR5 cell signaling pathways involved in normal brain aging from those implicated in HD.