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

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.

Ultrastructural Analysis of Thalamus Damages in a Mouse Model of Osmotic-Induced Demyelination

“…Following the development of a mouse model of ODS induced by the abrupt correction of a chronic hyponatremia, analysis of fine structural aspects has been able to verify some neuropathologic damages previously described at the EM level (Bouchat et al 2018). Many histopathologic similarities were found compared with the ODS rat model (Rojiani et al 1994) and the human case studies (Powers and McKeever 1976).…”

“…ODS 48 H Astrocytes from Caudate Putamen In order to strengthen these findings, the surveys of striatal astrocytes morphology found that no demyelinating lesions or cellular damages were noticed in the caudate putamen using light microscopy (Bouchat et al 2018). To further confirm these data, our observations obtained in and around the ODS thalamus lesions were compared with a morphologically undamaged The plus sign indicates present; the minus sign indicates absent central nervous system (CNS) area.…”

“…6e2, where an adjacent axon of the previously described altered astrocyte is fenced by its frothy myelin. Morphology alone could not decide about the type of cell death, but only preliminary data had suggested necroptosis, found in 12 h ODS oligodendrocytes and verified with immunohistochemical markers (Bouchat et al 2018).…”

“…ODS was induced in mice as described previously (Bouchat et al 2018). Briefly, an osmotic minipump (Model 1004, Alzet, Cupertino, CA, USA) filled with desmopressin acetate (0.002 mg/ml) (Minirin®, Ferring, Saint-Prex, Switzerland) was inserted subcutaneously at day 0.…”

“…In the present report, an in-depth ultrastructural analysis of the thalamus, a brain region prone to demyelination in ODS, was conducted following a previously developed mouse model (Bouchat et al 2018) and discussed in light of the ultrastructural findings described with regards of human case reports (Powers and McKeever 1976) and the rat model of ODS (Rojiani et al 1994). The morphological analysis has been focused on the relay thalamic nuclei-ventral posterolateral (VPL) and ventral posteromedial (VPM)-because of their susceptibility towards osmotic-induced demyelination (Bouchat et al 2018).…”