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Statins decrease dendritic arborization in rat sympathetic neurons by blocking RhoA activation.

ABSTRACT: Clinical and experimental evidence suggest that statins decrease sympathetic activity, but whether peripheral mechanisms involving direct actions on post-ganglionic sympathetic neurons contribute to this effect is not known. Because tonic activity of these neurons is directly correlated with the size of their dendritic arbor, we tested the hypothesis that statins decrease dendritic arborization in sympathetic neurons. Oral administration of atorvastatin (20 mg/kg/day for 7 days) significantly reduced dendritic arborization in vivo in sympathetic ganglia of adult male rats. In cultured sympathetic neurons, statins caused dendrite retraction and reversibly blocked bone morphogenetic protein-induced dendritic growth without altering cell survival or axonal growth. Supplementation with mevalonate or isoprenoids, but not cholesterol, attenuated the inhibitory effects of statins on dendritic growth, whereas specific inhibition of isoprenoid synthesis mimicked these statin effects. Statins blocked RhoA translocation to the membrane, an event that requires isoprenylation, and constitutively active RhoA reversed statin effects on dendrites. These observations that statins decrease dendritic arborization in sympathetic neurons by blocking RhoA activation suggest a novel mechanism by which statins decrease sympathetic activity and protect against cardiovascular and cerebrovascular disease.

SUBMITTER: Kim WY

PROVIDER: S-EPMC4277848 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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Statins decrease dendritic arborization in rat sympathetic neurons by blocking RhoA activation.

Kim Woo-Yang WY Gonsiorek Eugene A EA Barnhart Chris C Davare Monika A MA Engebose Abby J AJ Lauridsen Holly H Bruun Donald D Lesiak Adam A Wayman Gary G Bucelli Robert R Higgins Dennis D Lein Pamela J PJ

Journal of neurochemistry 20090201 4

Clinical and experimental evidence suggest that statins decrease sympathetic activity, but whether peripheral mechanisms involving direct actions on post-ganglionic sympathetic neurons contribute to this effect is not known. Because tonic activity of these neurons is directly correlated with the size of their dendritic arbor, we tested the hypothesis that statins decrease dendritic arborization in sympathetic neurons. Oral administration of atorvastatin (20 mg/kg/day for 7 days) significantly re ...[more]

PMID: 19209406

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Project description:BackgroundDendrites are the primary site of synapse formation in the vertebrate nervous system; however, relatively little is known about the molecular mechanisms that regulate the initial formation of primary dendrites. Embryonic rat sympathetic neurons cultured under defined conditions extend a single functional axon, but fail to form dendrites. Addition of bone morphogenetic proteins (BMPs) triggers these neurons to extend multiple dendrites without altering axonal growth or cell survival. We used this culture system to examine differential gene expression patterns in naïve vs. BMP-treated sympathetic neurons in order to identify candidate genes involved in regulation of primary dendritogenesis.Methodology/principal findingsTo determine the critical transcriptional window during BMP-induced dendritic growth, morphometric analysis of microtubule-associated protein (MAP-2)-immunopositive processes was used to quantify dendritic growth in cultures exposed to the transcription inhibitor actinomycin-D added at varying times after addition of BMP-7. BMP-7-induced dendritic growth was blocked when transcription was inhibited within the first 24 hr after adding exogenous BMP-7. Thus, total RNA was isolated from sympathetic neurons exposed to three different experimental conditions: (1) no BMP-7 treatment; (2) treatment with BMP-7 for 6 hr; and (3) treatment with BMP-7 for 24 hr. Affymetrix oligonucleotide microarrays were used to identify differential gene expression under these three culture conditions. BMP-7 significantly regulated 56 unique genes at 6 hr and 185 unique genes at 24 hr. Bioinformatic analyses implicate both established and novel genes and signaling pathways in primary dendritogenesis.Conclusions/significanceThis study provides a unique dataset that will be useful in generating testable hypotheses regarding transcriptional control of the initial stages of dendritic growth. Since BMPs selectively promote dendritic growth in central neurons as well, these findings may be generally applicable to dendritic growth in other neuronal cell types.

Dataset Information

Statins decrease dendritic arborization in rat sympathetic neurons by blocking RhoA activation.

Publications

Statins decrease dendritic arborization in rat sympathetic neurons by blocking RhoA activation.

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