Abstract
Hydrocephalus, characterized by ventriculomegaly due to cerebrospinal fluid accumulation in the cerebral ventricles, is a co-morbidity factor in several neurodevelopmental, psychiatric and neurodegenerative diseases. Aquaporin-4 (AQP4) is crucial for brain water homeostasis, with Aqp4 knockout mice showing sporadic ventriculomegaly and increased brain water content. Kinase D interacting substrate of 220 kDa (Kidins220), a transmembrane protein involved in neuronal survival, synaptic activity and neurogenesis, controls AQP4 levels in ependymocytes and brain astrocytes. Indeed, Kidins220 deficiency in mice leads to hydrocephalus by downregulating VPS35, a key component of the retromer complex, and targeting AQP4 to lysosomal degradation. Importantly, the ependymal barrier of idiopathic normal pressure hydrocephalus patients shows a similar downregulation of KIDINS220 and AQP4. In addition, pathogenic variants in the KIDINS220 gene are linked to SINO syndrome, a rare disorder characterized by spastic paraplegia, intellectual disability, nystagmus, and obesity associated with hydrocephalus and ventriculomegaly. Given the retina's structural and functional similarities to the brain, we hypothesized that Kidins220 deficiency would affect retinal water regulation. However, the diminished expression of Kidins220 and VPS35 in the retina of Kidins220-deficient hydrocephalus mice, did not cause edema or downregulate AQP4 in Müller cells. Surprisingly, there was an increase in AQP4 levels within this glial cell population. Conversely, AQP4 expression in the optic nerve astrocytes was reduced, as observed in brain astrocytes, suggesting a distinctive adaptive response to hydrocephalus in Müller glia within the Kidins220-deficient retina. Furthermore, we observed phenotypic modifications in retinal glia in Kidins220-deficient hydrocephalus mice. However, we did not find any signs of neuronal damage in the retina. Future studies using OCT and OCTA in SINO syndrome patients with ventriculomegaly will be essential in elucidating the relationship between KIDINS220 pathogenic variants, retinal alterations, papilledema, and visual function.