Myelin formation requires a process of proliferation and differentiation of oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes (OLs) (Sampaio-Baptista and Johansen-Berg, 2017). Myelin sheaths contain a compact and a non-compact component. Myelin basic protein (MBP) and myelin proteolipid protein (PLP) contribute to the compaction and stability of the myelin sheath (Raasakka and Kursula, 2020), whereas 2′,3′-cyclic nucleotide 3′ phosphodiesterase (CNP) and myelin oligodendrocyte glycoprotein (MOG) are found in the non-compact domains of myelin sheaths (Raasakka and Kursula, 2020; Snaidero et al., 2017). Under physiological conditions, WM plasticity requires myelin renewal of existing myelin sheaths and myelination of damaged axons (Alizadeh et al., 2015). However, in some pathological conditions, including hydrocephalus, the remyelinating process can be ineffective, delayed, or halted (Ayannuga et al., 2016).

Normal pressure hydrocephalus (NPH) is a neurological condition that occurs in elderly patients and is caused by an abnormal change in the production, circulation, and absorption of cerebrospinal fluid (CSF) that expands the ventricular system. The main treatment for hydrocephalus is the surgical implantation of a drainage system, referred to as a shunt, which derives the CSF to the abdominal cavity (Reddy et al., 2014; Sundström et al., 2017). In NPH patients, several abnormalities in the corpus callosum (CC) and white matter (WM) regions have been observed, including scalloping, lifting, stretching, and thinning (Campos-Ordoñez et al., 2014; Kanno et al., 2017; Lane et al., 2001). Experimental evidence indicates that hydrocephalus reduces the size of the corpus callosum (da Silva Lopes et al., 2009; 1997; Di Curzio et al., 2013), causes cellular edema, and promotes gliosis without overt white matter lesions (da Silva Lopes et al., 2009). However, some authors sustain that these WM changes can depend on the time and degree of ventriculomegaly (Olopade et al., 2012), and remain after hydrocephalus treatment (Kanno et al., 2017; Mataró et al., 2007). In rats, 9-month chronic hydrocephalus produces significant motor deficits that are accompanied by thinning of the CC and myelin damage, some of these alterations are also observed in humans (Del Bigio et al., 2003). This evidence supports the notion that long-lasting NPH can damage WM structures. However, the cellular and molecular mechanisms underlying these WM alterations remain unclear. In addition, it is also unknown whether the cellular alterations are already present in hydrocephalus before the behavioral manifestations occur.

In this study, we assessed whether a 60- or 120-d hydrocephalus disrupts the cytoarchitecture, oligodendrocyte lineage, and myelin integrity of the CC of mice. To establish whether these changes may be reversible, we analyzed an additional 60-NPH group in which hydrocephalus was surgically treated. This mouse model produces highly reproducible normotensive hydrocephalus, which is reversible after removing the obstructive device (Campos-ordonez and Gonzalez-perez, 2021). Our data indicate that NPH produces severe changes in the proliferation and survival of oligodendrocytes, even before there is any symptomatic evidence. Intriguingly, most of these pathological changes are not reversible upon hydrocephalus resolution. Understanding the cellular alterations and the precise time-point to provide early treatment for ventriculomegaly is a crucial step for the design of therapies that may help reduce the impact of hydrocephalus on the WM of patients.