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Astrocytic ?2 Adrenergic Receptor Gene Deletion Affects Memory in Aged Mice.

ABSTRACT: In vitro and in vivo studies suggest that the astrocytic adrenergic signalling enhances glycogenolysis which provides energy to be transported to nearby cells and in the form of lactate. This energy source is important for motor and cognitive functioning. While it is suspected that the ?2-adrenergic receptor on astrocytes might contribute to this energy balance, it has not yet been shown conclusively in vivo. Inducible astrocyte specific ?2-adrenergic receptor knock-out mice were generated by crossing homozygous ?2-adrenergic receptor floxed mice (Adrb2flox) and mice with heterozygous tamoxifen-inducible Cre recombinase-expression driven by the astrocyte specific L-glutamate/L-aspartate transporter promoter (GLAST-CreERT2). Assessments using the modified SHIRPA (SmithKline/Harwell/Imperial College/Royal Hospital/Phenotype Assessment) test battery, swimming ability test, and accelerating rotarod test, performed at 1, 2 and 4 weeks, 6 and 12 months after tamoxifen (or vehicle) administration did not reveal any differences in physical health or motor functions between the knock-out mice and controls. However deficits were found in the cognitive ability of aged, but not young adult mice, reflected in impaired learning in the Morris Water Maze. Similarly, long-term potentiation (LTP) was impaired in hippocampal brain slices of aged knock-out mice maintained in low glucose media. Using microdialysis in cerebellar white matter we found no significant differences in extracellular lactate or glucose between the young adult knock-out mice and controls, although trends were detected. Our results suggest that ?2-adrenergic receptor expression on astrocytes in mice may be important for maintaining cognitive health at advanced age, but is dispensable for motor function.

SUBMITTER: Jensen CJ

PROVIDER: S-EPMC5077086 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Astrocytic β2 Adrenergic Receptor Gene Deletion Affects Memory in Aged Mice.

Jensen Cathy Joanna CJ Demol Frauke F Bauwens Romy R Kooijman Ron R Massie Ann A Villers Agnès A Ris Laurence L De Keyser Jacques J

PloS one 20161024 10

In vitro and in vivo studies suggest that the astrocytic adrenergic signalling enhances glycogenolysis which provides energy to be transported to nearby cells and in the form of lactate. This energy source is important for motor and cognitive functioning. While it is suspected that the β2-adrenergic receptor on astrocytes might contribute to this energy balance, it has not yet been shown conclusively in vivo. Inducible astrocyte specific β2-adrenergic receptor knock-out mice were generated by cr ...[more]

PMID: 27776147

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Project description:Abstract The anabolic response of aged bone to skeletal loading is typically poor. Efforts to improve mechanotransduction in aged bone have met with limited success. This study investigated whether the bone response to direct skeletal loading is improved by reducing sympathetic suppression of osteoblastic bone formation via β2AR. To test this possibility, we treated aged wild‐type C57BL/6 mice with a selective β2AR antagonist, butaxamine (Butax), before each of nine bouts of cantilever bending of the right tibia. Midshaft periosteal bone formation was assessed by dynamic histomorphometry of loaded and contralateral tibias. Butax treatment did not alter osteoblast activity of contralateral tibias. Loading alone induced a modest but significant osteogenic response. However, when loading was combined with Butax pretreatment, the anabolic response was significantly elevated compared with loading preceded by saline injection. Subsequent studies in osteoblastic cultures revealed complex negative interactions between adrenergic and mechanically induced intracellular signaling. Activation of β2AR by treatment with the β1, β2‐agonist isoproterenol (ISO) before fluid flow exposure diminished mechanically stimulated ERK1/2 phosphorylation in primary bone cell outgrowth cultures and AKT phosphorylation in MC3T3‐E1 pre‐osteoblast cultures. Expression of mechanosensitive Fos and Ptgs2 genes was enhanced with ISO treatment and reduced with flow in both MC3T3‐E1 and primary cultures. Finally, co‐treatment of MC3T3‐E1 cells with Butax reversed these ISO effects, confirming a critical role for β2AR in these responses. In combination, these results demonstrate that selective inhibition of β2AR is sufficient to enhance the anabolic response of the aged skeleton to loading, potentially via direct effects upon osteoblasts. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Project description:BackgroundThe NF-?B signaling pathway orchestrates many of the intricate aspects of neuroinflammation. Astrocytic ??-adrenergic receptors have emerged as potential regulators in central nervous system inflammation and are potential targets for pharmacological modulation. The aim of this study was to elucidate the crosstalk between astrocytic ??-adrenergic receptors and the TNF-? induced inflammatory gene program.MethodsProinflammatory conditions were generated by the administration of TNF-?. Genes that are susceptible to astrocytic crosstalk between ??-adrenergic receptors (stimulated by clenbuterol) and TNF-? were identified by qPCR-macroarray-based gene expression analysis in a human 1321 N1 astrocytoma cell line. Transcriptional patterns of the identified genes in vitro were validated by RT-PCR on the 1321 N1 cell line as well as on primary rat astrocytes. In vivo expression patterns were examined by intracerebroventricular administration of clenbuterol and/or TNF-? in rats. To examine the impact on the inflammatory cell content of the brain we performed extensive FACS analysis of rat brain immune cells after intracerebroventricular clenbuterol and/or TNF-? administration.ResultsParallel transcriptional patterns in vivo and in vitro confirmed the relevance of astrocytic ??-adrenergic receptors as modulators of brain inflammatory responses. Importantly, we observed pronounced effects of ?2-adrenergic receptor agonists and TNF-? on IL-6, CXCL2, CXCL3, VCAM1, and ICAM1 expression, suggesting a role in inflammatory brain cell homeostasis. Extensive FACS-analysis of inflammatory cell content in the brain demonstrated that clenbuterol/TNF-? co-administration skewed the T cell population towards a double negative phenotype and induced a shift in the myeloid brain cell population towards a neutrophilic predominance.ConclusionsOur results show that astrocytic ??-adrenergic receptors are potent regulators of astrocytic TNF-?-activated genes in vitro and in vivo, and ultimately modulate the molecular network involved in the homeostasis of inflammatory cells in the central nervous system. Astrocytic ??-adrenergic receptors and their downstream signaling pathway may serve as potential targets to modulate neuroinflammatory responses.

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Astrocytic ?2 Adrenergic Receptor Gene Deletion Affects Memory in Aged Mice.

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Astrocytic β2 Adrenergic Receptor Gene Deletion Affects Memory in Aged Mice.

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