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MGluR5 ablation leads to age-related synaptic plasticity impairments and does not improve Huntington's disease phenotype.

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.

SUBMITTER: de Souza JM

PROVIDER: S-EPMC9148310 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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mGluR5 ablation leads to age-related synaptic plasticity impairments and does not improve Huntington's disease phenotype.

de Souza Jessica M JM Ferreira-Vieira Talita H TH Maciel Esther M A EMA Silva Nathalia C NC Lima Izabella B Quirino IBQ Doria Juliana G JG Olmo Isabella G IG Ribeiro Fabiola M FM

Scientific reports 20220528 1

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<sup>-/-</sup>, BACHD, which is a mouse model of Huntington's Disease (HD), and mGluR5<sup>-/-</sup>/BACHD ...[more]

PMID: 35643779

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Project description:Neuroinflammation plays an important role in the onset and progression of neurodegenerative diseases such as Alzheimer's disease. Lipopolysaccharide (LPS, endotoxin) levels are higher in the brains of Alzheimer's disease patients and are associated with neuroinflammation and cognitive decline, while neural cholinergic signaling controls inflammation. This study aimed to examine the efficacy of galantamine, a clinically approved cholinergic agent, in alleviating LPS-induced neuroinflammation and cognitive decline as well as the associated mechanism.Mice were treated with galantamine (4 mg/kg, intraperitoneal injection) for 14 days prior to LPS exposure (intracerebroventricular injection). Cognitive tests were performed, including the Morris water maze and step-through tests. mRNA expression of the microglial marker (CD11b), astrocytic marker (GFAP), and pro-inflammatory cytokines (IL-1?, IL-6, and TNF-?) were examined in the hippocampus by quantitative RT-PCR. The inflammatory signaling molecule, nuclear factor-kappa B (NF-?B p65), and synapse-associated proteins (synaptophysin, SYN, and postsynaptic density protein 95, PSD-95) were examined in the hippocampus by western blotting. Furthermore, NF-?B p65 levels in microglial cells and hippocampal neurons were examined in response to LPS and galantamine.Galantamine treatment prevented LPS-induced deficits in spatial learning and memory as well as memory acquisition of the passive avoidance response. Galantamine decreased the expression of microglia and astrocyte markers (CD11b and GFAP), pro-inflammatory cytokines (IL-1?, IL-6, and TNF-?), and NF-?B p65 in the hippocampus of LPS-exposed mice. Furthermore, galantamine ameliorated LPS-induced loss of synapse-associated proteins (SYN and PSD-95) in the hippocampus. In the in vitro study, LPS increased NF-?B p65 levels in microglia (BV-2 cells); the supernatant of LPS-stimulated microglia (Mi-sup), but not LPS, decreased the viability of hippocampal neuronal cells (HT-22 cells) and increased NF-?B p65 levels as well as expression of pro-inflammatory cytokines (IL-1?, IL-6) in HT-22 cells. Importantly, galantamine reduced the inflammatory response not only in the BV-2 microglia cell line, but also in the HT-22 hippocampal neuronal cell line.These findings indicate that galantamine could be a promising treatment to improve endotoxin-induced cognitive decline and neuroinflammation in neurodegenerative diseases.

Dataset Information

MGluR5 ablation leads to age-related synaptic plasticity impairments and does not improve Huntington's disease phenotype.

Publications

mGluR5 ablation leads to age-related synaptic plasticity impairments and does not improve Huntington's disease phenotype.

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