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Cholesterol regulates polymodal sensory transduction in Muller glia.

ABSTRACT: Over- and underexposure to cholesterol activates glia in neurodegenerative brain and retinal diseases but the molecular targets of cholesterol in glial cells are not known. Here, we report that disruption of unesterified membrane cholesterol content modulates the transduction of chemical, mechanical and temperature stimuli in mouse Müller cells. Activation of TRPV4 (transient receptor potential vanilloid type 4), a nonselective polymodal cation channel was studied following the removal or supplementation of cholesterol using the methyl-beta cyclodextrin (M?CD) delivery vehicle. Cholesterol extraction disrupted lipid rafts and caveolae without affecting TRPV4 trafficking or membrane localization protein. However, M?CD suppressed agonist (GSK1016790A)- and temperature-evoked elevations in [Ca2+ ]i , and suppressed transcellular propagation of Ca2+ waves. Lowering the free membrane cholesterol content markedly prolonged the time-course of the glial swelling response, whereas M?CD:cholesterol supplementation enhanced agonist- and temperature-induced Ca2+ signals and shortened the swelling response. Taken together, these data show that membrane cholesterol modulates polymodal transduction of agonists, swelling and temperature stimuli in retinal radial glia and suggest that dyslipidemic retinas might be associated with abnormal glial transduction of ambient sensory inputs.

SUBMITTER: Lakk M

PROVIDER: S-EPMC5761668 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Cholesterol regulates polymodal sensory transduction in Müller glia.

Lakk Monika M Yarishkin Oleg O Baumann Jackson M JM Iuso Anthony A Križaj David D

Glia 20170830 12

Over- and underexposure to cholesterol activates glia in neurodegenerative brain and retinal diseases but the molecular targets of cholesterol in glial cells are not known. Here, we report that disruption of unesterified membrane cholesterol content modulates the transduction of chemical, mechanical and temperature stimuli in mouse Müller cells. Activation of TRPV4 (transient receptor potential vanilloid type 4), a nonselective polymodal cation channel was studied following the removal or supple ...[more]

PMID: 28856727

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Project description:BackgroundAvoidance of noxious stimuli is essential for the survival of an animal in its natural habitat. Some avoidance responses require polymodal sensory neurons, which sense a range of diverse stimuli, whereas other stimuli require a unimodal sensory neuron, which senses a single stimulus. Polymodality might have evolved to help animals quickly detect and respond to diverse noxious stimuli. Nematodes inhabit diverse habitats and most nematode nervous systems are composed of a small number of neurons, despite a wide assortment in nematode sizes. Given this observation, we speculated that cellular contribution to stereotyped avoidance behaviors would also be conserved between nematode species. The ASH neuron mediates avoidance of three classes of noxious stimuli in Caenorhabditis elegans. Two species of parasitic nematodes also utilize the ASH neuron to avoid certain stimuli. We wanted to extend our knowledge of avoidance behaviors by comparing multiple stimuli in a set of free-living nematode species.ResultsWe used comparative behavioral analysis and laser microsurgery to examine three avoidance behaviors in six diverse species of free-living nematodes. We found that all species tested exhibit avoidance of chemo-, mechano- and osmosensory stimuli. In C. elegans, the bilaterally symmetric polymodal ASH neurons detect all three classes of repellant. We identified the putative ASH neurons in different nematode species by their anatomical positions and showed that in all six species ablation of the ASH neurons resulted in an inability to avoid noxious stimuli. However, in the nematode Pristionchus pacificus, the ADL neuron in addition to the ASH neuron contributed to osmosensation. In the species Caenorhabditis sp. 3, only the ASH neuron was required to mediate nose touch avoidance instead of three neurons in C. elegans. These data suggest that different species can increase or decrease the contribution of additional, non-ASH sensory neurons mediating osmosensation and mechanosensation.ConclusionThe overall conservation of ASH mediated polymodal nociception suggests that it is an ancestral evolutionarily stable feature of sensation. However, the finding that contribution from non-ASH sensory neurons mediates polymodal nociception in some nematode species suggests that even in conserved sensory behaviors, the cellular response network is dynamic over evolutionary time, perhaps shaped by adaptation of each species to its environment.

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Cholesterol regulates polymodal sensory transduction in Muller glia.

Publications

Cholesterol regulates polymodal sensory transduction in Müller glia.

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