Behavioural alterations and morphological changes are attenuated by the lack of TRPA1 receptors in the cuprizone-induced demyelination model in mice

Bölcskei, Kata; Kriszta, Gábor; Sághy, Éva; Payrits, Maja; Sipos, Éva; Vranesics, Anett; Berente, Zoltán; Ábrahám, Hajnalka; Ács, Pongrác; Komoly, Sámuel; Pintér, Erika

doi:10.1016/j.jneuroim.2018.03.020

Cited by 41 publications

(37 citation statements)

References 35 publications

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“…The most pronounced difference was detected on the 4th week, but the disparity decreased at later time points. In our previous study in the cuprizone model with embryonic global TRPA1 KO mice, we provided MRI-based evidence that the severity of myelin loss in the gene-deleted animals was significantly lower at all measurement points during the six-week experiment compared to the wild-type controls [23]. In accordance with the present results, the largest differences in signal intensities were detected on the 3rd and 4th weeks.…”

Section: Discussionsupporting

confidence: 91%

“…Feeding mice with cuprizone leads to a well-reproducible demyelination of the corpus callosum as well as other subcortical and cortical brain areas by inducing oligodendrocyte apoptosis and a secondary activation of astrocytes and microglia [15,16,[18][19][20][21]. We have revealed that demyelination of the corpus callosum was significantly reduced in TRPA1 receptor gene-deleted mice [22,23]. Based on our data we have assumed that TRPA1 receptors localized on astrocytes may influence the astrocyte-oligodendrocyte crosstalk.…”

mentioning

confidence: 70%

“…Cuprizone was administered orally for 6 weeks as previously described [22,23]. Briefly, standard rodent chow was ground and 0.2% cuprizone was thoroughly mixed into ground chow which was placed into the cages in small ceramic bowls.…”

Section: Cuprizone Treatmentmentioning

confidence: 99%

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Investigation of Cuprizone-Induced Demyelination in mGFAP-Driven Conditional Transient Receptor Potential Ankyrin 1 (TRPA1) Receptor Knockout Mice

Kriszta

Nemes

Szepes

et al. 2019

Cells

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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 (TRPA1 Fl/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 +/− TRPA1 Fl/Fl ) and heterozygous (GFAP-Cre +/− TRPA1 Fl/− ) 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.Cells 2020, 9, 81 2 of 13 and oxidized lipid molecules [1][2][3]. Apart from being a nocisensor for exogenous irritant compounds, it has been suggested to work as a sensor for oxidative stress [4]. Originally described to be localized on a subgroup of nociceptive primary afferent neurons [5,6], it was later revealed that TRPA1 is also expressed at lower levels by various non-neuronal cells including keratinocytes, endothelial cells and cells of the gastrointestinal mucosa [1-3,7]. More importantly, 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].In astrocytes, TRPA1 receptors were implicated in both physiological and pathophysiological processes. Astrocyte TRPA1 receptors were shown to regulate resting Ca 2+ levels and modulate GABA-ergic inhibitory transmission by reducing GABA transport [8]. TRPA1 receptors on astrocytes were also suggested to play a role in long-term potentiation in the mouse hippocampus [9]. Since reactive astrocytes can contribute to the progression of neuroinflammation in neurodegenerative diseases [13,14], several workgroups, including ours, had started to investigate the role of TRPA1 in animal models of neurodegenerative diseases. Our previous study aimed at examining the role of TRPA1 in the cuprizone-induced demyelination model in mice. Cuprizone...

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Section: Discussionsupporting

confidence: 91%

mentioning

confidence: 70%

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Investigation of Cuprizone-Induced Demyelination in mGFAP-Driven Conditional Transient Receptor Potential Ankyrin 1 (TRPA1) Receptor Knockout Mice

Kriszta

Nemes

Szepes

et al. 2019

Cells

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“…It is therefore important to consider that, apart from restored memory skills of mice in the NOR test, anxiety-like behavior in the EPM test and loss of frequency discrimination in the auditory Pavlovian conditioning paradigm were still present upon myelin gain. Similarly, the distance travelled in the OF test was also altered after myelin loss, supporting other recent findings (Bölcskei et al, 2018). The network-based approach applied here bridges ex vivo tracked tissue dynamics and in vivo microanatomy upon myelin loss and renewal, shaping discrete determinants of behavioral adaptive responses.…”

Section: Discussionsupporting

confidence: 85%

Myelination- and immune mediated MR-based brain network correlates

Cerina

Gallus

Koirala³

et al. 2020

Preprint

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Background: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS), characterized by inflammatory and neurodegenerative processes. Despite demyelination being a hallmark of the disease, how it relates to neurodegeneration has still not been completely unraveled, and research is still ongoing into how these processes can be tracked non-invasively. Magnetic resonance imaging (MRI) derived brain network characteristics, which closely mirror disease processes and relate to functional impairment, recently became important variables for characterizing immune-mediated neurodegeneration, however their histopathological basis remains unclear. Methods: In order to determine the MRI-derived correlates of myelin dynamics and to test if brain network characteristics derived from diffusion tensor imaging reflect microstructural tissue reorganization, we took advantage of the cuprizone model of general demyelination in mice and performed longitudinal histological and imaging analyses with behavioral tests. By introducing cuprizone into the diet, we induced targeted and consistent demyelination of oligodendrocytes, over a period of 5 weeks. Subsequent myelin synthesis was enabled by reintroduction of normal food. Results: Using specific immune-histological markers, we demonstrated that two weeks of cuprizone diet induced a 52% reduction of myelin content in the corpus callosum (CC) and a 35% reduction in the neocortex. An extended cuprizone diet increased myelin loss in the CC, while remyelination commenced in the neocortex. These histologically determined dynamics were reflected by MRI measurements from diffusion tensor imaging. Demyelination was associated with decreased fractional anisotropy (FA) values and increased modularity and clustering at the network level. MRI-derived modularization of the brain network and FA reduction in key anatomical regions, including the hippocampus, thalamus and analyzed cortical areas, were closely related to impaired memory function and anxiety-like behavior. Conclusion: Network specific remyelination, shown by histology and MRI metrics, determined amelioration of functional performance and neuropsychiatric symptoms. Taken together, we illustrate the histological basis for the MRI-driven network responses to demyelination, where increased modularity leads to evolving damage and abnormal behavior in MS. Quantitative information about in vivo myelination processes is mirrored by diffusion based imaging of microstructural integrity and network characteristics.

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“…Although strong immunolabelling of TRPA1 in astrocytes and reactive astrocytes has been shown [107], this TRPA1 antibody strongly colocalises with GFAP even in TRPA1 knockouts (our unpublished observations). Therefore, the protective effect of TRPA1 knockout in the cuprizone model [107,111] may reflect protection from TRPA1 expression in either astrocytes or oligodendrocytes, or both. Importantly, like some other TRP channels, TRPA1 expression is upregulated during inflammation [104,112,113], and therefore it may be important to measure TRPA1 expression in single cells during disease, to determine whether it plays a greater role than predicted by sequencing data from cells in healthy animals.…”

Section: A C C E P T E Dmentioning

confidence: 99%