Regional oligodendrocytopathy and astrocytopathy precede myelin loss and blood–brain barrier disruption in a murine model of osmotic demyelination syndrome

Joanna Bouchat, Bruno Couturier, Catherine Marneffe, Fabrice Gankam Kengne, Benoît Balau, Kathleen De Swert, Luc Poncelet, Jean Pierre Brion, Jacques Gilloteaux, Charles Nicaise

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Résumé

The osmotic demyelination syndrome (ODS) is a non-primary inflammatory disorder of the central nervous system myelin that is often associated with a precipitous rise of serum sodium concentration. To investigate the physiopathology of ODS in vivo, we generated a novel murine model based on the abrupt correction of chronic hyponatremia. Accordingly, ODS mice developed impairments in brainstem auditory evoked potentials and in grip strength. At 24 hr post-correction, oligodendrocyte markers (APC and Cx47) were downregulated, prior to any detectable demyelination. Oligodendrocytopathy was temporally and spatially correlated with the loss of astrocyte markers (ALDH1L1 and Cx43), and both with the brain areas that will develop demyelination. Oligodendrocytopathy and astrocytopathy were confirmed at the ultrastructural level and culminated with necroptotic cell death, as demonstrated by pMLKL immunoreactivity. At 48 hr post-correction, ODS brains contained pathognomonic demyelinating lesions in the pons, mesencephalon, thalamus and cortical regions. These damages were accompanied by blood–brain barrier (BBB) leakages. Expression levels of IL-1β, FasL, TNFRSF6 and LIF factors were significantly upregulated in the ODS lesions. Quiescent microglial cells type A acquired an activated type B morphology within 24 hr post-correction, and reached type D at 48 hr. In conclusion, this murine model of ODS reproduces the CNS demyelination observed in human pathology and indicates ambiguous causes that is regional vulnerability of oligodendrocytes and astrocytes, while it discards BBB disruption as a primary cause of demyelination. This study also raises new queries about the glial heterogeneity in susceptible brain regions as well as about the early microglial activation associated with ODS.

langue originaleAnglais
Pages (de - à)606-622
Nombre de pages17
journalGlia
Volume66
Numéro de publication3
Date de mise en ligne précoce2017
Les DOIs
étatPublié - 1 mars 2018

Empreinte digitale

Demyelinating Diseases
Myelin Sheath
Oligodendroglia
Astrocytes
Brain
Connexin 43
Pons
Brain Stem Auditory Evoked Potentials
Hyponatremia
Central Nervous System Diseases
Hand Strength
Mesencephalon
Thalamus
Interleukin-1
Neuroglia
Cell Death
Down-Regulation
Sodium
Pathology

Citer ceci

Bouchat, Joanna ; Couturier, Bruno ; Marneffe, Catherine ; Gankam Kengne, Fabrice ; Balau, Benoît ; De Swert, Kathleen ; Poncelet, Luc ; Brion, Jean Pierre ; Gilloteaux, Jacques ; Nicaise, Charles. / Regional oligodendrocytopathy and astrocytopathy precede myelin loss and blood–brain barrier disruption in a murine model of osmotic demyelination syndrome. Dans: Glia. 2018 ; Vol 66, Numéro 3. p. 606-622.
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abstract = "The osmotic demyelination syndrome (ODS) is a non-primary inflammatory disorder of the central nervous system myelin that is often associated with a precipitous rise of serum sodium concentration. To investigate the physiopathology of ODS in vivo, we generated a novel murine model based on the abrupt correction of chronic hyponatremia. Accordingly, ODS mice developed impairments in brainstem auditory evoked potentials and in grip strength. At 24 hr post-correction, oligodendrocyte markers (APC and Cx47) were downregulated, prior to any detectable demyelination. Oligodendrocytopathy was temporally and spatially correlated with the loss of astrocyte markers (ALDH1L1 and Cx43), and both with the brain areas that will develop demyelination. Oligodendrocytopathy and astrocytopathy were confirmed at the ultrastructural level and culminated with necroptotic cell death, as demonstrated by pMLKL immunoreactivity. At 48 hr post-correction, ODS brains contained pathognomonic demyelinating lesions in the pons, mesencephalon, thalamus and cortical regions. These damages were accompanied by blood–brain barrier (BBB) leakages. Expression levels of IL-1β, FasL, TNFRSF6 and LIF factors were significantly upregulated in the ODS lesions. Quiescent microglial cells type A acquired an activated type B morphology within 24 hr post-correction, and reached type D at 48 hr. In conclusion, this murine model of ODS reproduces the CNS demyelination observed in human pathology and indicates ambiguous causes that is regional vulnerability of oligodendrocytes and astrocytes, while it discards BBB disruption as a primary cause of demyelination. This study also raises new queries about the glial heterogeneity in susceptible brain regions as well as about the early microglial activation associated with ODS.",
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author = "Joanna Bouchat and Bruno Couturier and Catherine Marneffe and {Gankam Kengne}, Fabrice and Beno{\^i}t Balau and {De Swert}, Kathleen and Luc Poncelet and Brion, {Jean Pierre} and Jacques Gilloteaux and Charles Nicaise",
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Bouchat, J, Couturier, B, Marneffe, C, Gankam Kengne, F, Balau, B, De Swert, K, Poncelet, L, Brion, JP, Gilloteaux, J & Nicaise, C 2018, 'Regional oligodendrocytopathy and astrocytopathy precede myelin loss and blood–brain barrier disruption in a murine model of osmotic demyelination syndrome', Glia, VOL. 66, Numéro 3, p. 606-622. https://doi.org/10.1002/glia.23268

Regional oligodendrocytopathy and astrocytopathy precede myelin loss and blood–brain barrier disruption in a murine model of osmotic demyelination syndrome. / Bouchat, Joanna; Couturier, Bruno; Marneffe, Catherine; Gankam Kengne, Fabrice; Balau, Benoît; De Swert, Kathleen; Poncelet, Luc; Brion, Jean Pierre; Gilloteaux, Jacques; Nicaise, Charles.

Dans: Glia, Vol 66, Numéro 3, 01.03.2018, p. 606-622.

Résultats de recherche: Contribution à un journal/une revueArticle

TY - JOUR

T1 - Regional oligodendrocytopathy and astrocytopathy precede myelin loss and blood–brain barrier disruption in a murine model of osmotic demyelination syndrome

AU - Bouchat, Joanna

AU - Couturier, Bruno

AU - Marneffe, Catherine

AU - Gankam Kengne, Fabrice

AU - Balau, Benoît

AU - De Swert, Kathleen

AU - Poncelet, Luc

AU - Brion, Jean Pierre

AU - Gilloteaux, Jacques

AU - Nicaise, Charles

PY - 2018/3/1

Y1 - 2018/3/1

N2 - The osmotic demyelination syndrome (ODS) is a non-primary inflammatory disorder of the central nervous system myelin that is often associated with a precipitous rise of serum sodium concentration. To investigate the physiopathology of ODS in vivo, we generated a novel murine model based on the abrupt correction of chronic hyponatremia. Accordingly, ODS mice developed impairments in brainstem auditory evoked potentials and in grip strength. At 24 hr post-correction, oligodendrocyte markers (APC and Cx47) were downregulated, prior to any detectable demyelination. Oligodendrocytopathy was temporally and spatially correlated with the loss of astrocyte markers (ALDH1L1 and Cx43), and both with the brain areas that will develop demyelination. Oligodendrocytopathy and astrocytopathy were confirmed at the ultrastructural level and culminated with necroptotic cell death, as demonstrated by pMLKL immunoreactivity. At 48 hr post-correction, ODS brains contained pathognomonic demyelinating lesions in the pons, mesencephalon, thalamus and cortical regions. These damages were accompanied by blood–brain barrier (BBB) leakages. Expression levels of IL-1β, FasL, TNFRSF6 and LIF factors were significantly upregulated in the ODS lesions. Quiescent microglial cells type A acquired an activated type B morphology within 24 hr post-correction, and reached type D at 48 hr. In conclusion, this murine model of ODS reproduces the CNS demyelination observed in human pathology and indicates ambiguous causes that is regional vulnerability of oligodendrocytes and astrocytes, while it discards BBB disruption as a primary cause of demyelination. This study also raises new queries about the glial heterogeneity in susceptible brain regions as well as about the early microglial activation associated with ODS.

AB - The osmotic demyelination syndrome (ODS) is a non-primary inflammatory disorder of the central nervous system myelin that is often associated with a precipitous rise of serum sodium concentration. To investigate the physiopathology of ODS in vivo, we generated a novel murine model based on the abrupt correction of chronic hyponatremia. Accordingly, ODS mice developed impairments in brainstem auditory evoked potentials and in grip strength. At 24 hr post-correction, oligodendrocyte markers (APC and Cx47) were downregulated, prior to any detectable demyelination. Oligodendrocytopathy was temporally and spatially correlated with the loss of astrocyte markers (ALDH1L1 and Cx43), and both with the brain areas that will develop demyelination. Oligodendrocytopathy and astrocytopathy were confirmed at the ultrastructural level and culminated with necroptotic cell death, as demonstrated by pMLKL immunoreactivity. At 48 hr post-correction, ODS brains contained pathognomonic demyelinating lesions in the pons, mesencephalon, thalamus and cortical regions. These damages were accompanied by blood–brain barrier (BBB) leakages. Expression levels of IL-1β, FasL, TNFRSF6 and LIF factors were significantly upregulated in the ODS lesions. Quiescent microglial cells type A acquired an activated type B morphology within 24 hr post-correction, and reached type D at 48 hr. In conclusion, this murine model of ODS reproduces the CNS demyelination observed in human pathology and indicates ambiguous causes that is regional vulnerability of oligodendrocytes and astrocytes, while it discards BBB disruption as a primary cause of demyelination. This study also raises new queries about the glial heterogeneity in susceptible brain regions as well as about the early microglial activation associated with ODS.

KW - astrocyte

KW - blood–brain barrier

KW - mice

KW - microglia

KW - oligodendrocyte

KW - osmotic demyelination syndrome

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U2 - 10.1002/glia.23268

DO - 10.1002/glia.23268

M3 - Article

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VL - 66

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