Abstract
Transient receptor potential ankyrin 1 (TRPA1) receptors are non-selective cation channels responsive to a variety of exogenous irritants and endogenous stimuli including products of oxidative stress. It is mainly expressed by primary sensory neurons; however, expression of TRPA1 by astrocytes and oligodendrocytes has recently been detected in the mouse brain. Genetic deletion of TRPA1 was shown to attenuate cuprizone-induced oligodendrocyte apoptosis and myelin loss in mice. In the present study we aimed at investigating mGFAP-Cre conditional TRPA1 knockout mice in the cuprizone model. These animals were generated by crossbreeding GFAP-Cre+/− and floxed TRPA1 (TRPA1Fl/Fl) mice. Cuprizone was administered for 6 weeks and demyelination was followed by magnetic resonance imaging (MRI). At the end of the treatment, demyelination and glial activation was also investigated by histological methods. The results of the MRI showed that demyelination was milder at weeks 3 and 4 in both homozygous (GFAP-Cre+/− TRPA1Fl/Fl) and heterozygous (GFAP-Cre+/− TRPA1Fl/−) conditional knockout animals compared to Cre−/− control mice. However, by week 6 of the treatment the difference was not detectable by either MRI or histological methods. In conclusion, TRPA1 receptors on astrocytes may transiently contribute to the demyelination induced by cuprizone, however, expression and function of TRPA1 receptors by other cells in the brain (oligodendrocytes, microglia, neurons) warrant further investigation.
Highlights
Transient receptor potential ankyrin 1 (TRPA1) receptors are non-selective cation channels which are responsive to a variety of exogenous and endogenous stimuli including mustard oil, cinnamaldehyde, irritant chemicals such as formalin or acrolein, as well as reactive oxygen speciesCells 2020, 9, 81; doi:10.3390/cells9010081 www.mdpi.com/journal/cellsCells 2020, 9, 81 and oxidized lipid molecules [1,2,3]
Intact TRPA1 mRNA levels were determined by quantitative RT-PCR in brain samples of glial fibrillary acidic protein (GFAP)-Cre-/- TRPA1Fl/Fl compared to GFAP-Cre+/- TRPA1Fl/- and GFAP-Cre+/- TRPA1Fl/Fl mice
Compared to GFAP-Cre−/− control mice where TRPA1 expression level was 102 ± 22%, both the GFAP-Cre+/− TRPA1Fl/− and GFAP-Cre+/− TRPA1Fl/Fl mouse groups had lower expression levels, 68 ± 28% and 77 ± 23%, respectively. These results indicate that some of the TRPA1 mRNA was lost due to Cre-LoxP recombination in both GFAP-Cre+/− groups
Summary
Transient receptor potential ankyrin 1 (TRPA1) receptors are non-selective cation channels which are responsive to a variety of exogenous and endogenous stimuli including mustard oil, cinnamaldehyde, irritant chemicals such as formalin or acrolein, as well as reactive oxygen speciesCells 2020, 9, 81; doi:10.3390/cells9010081 www.mdpi.com/journal/cellsCells 2020, 9, 81 and oxidized lipid molecules [1,2,3]. Described to be localized on a subgroup of nociceptive primary afferent neurons [5,6], it was later revealed that TRPA1 is expressed at lower levels by various non-neuronal cells including keratinocytes, endothelial cells and cells of the gastrointestinal mucosa [1,2,3,7]. Several studies have supported the presence of TRPA1 receptors in the brain on astrocytes [8,9,10], as well as oligodendrocytes [11]. A recent cell-specific transcriptome analysis of the mouse cortex revealed low level expression of TRPA1 on neurons, astrocytes, oligodendrocytes and microglia, as well [12]. Astrocyte TRPA1 receptors were shown to regulate resting Ca2+ levels and modulate
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