Trillo-Contreras, José LuisToledo-Aral, Juan JoséVilladiego, JavierEchevarría, Miriam2022-11-252022-11-252021-09-09Trillo-Contreras JL, Toledo-Aral JJ, Villadiego J, Echevarría M. Aquaporin-4 Mediates Permanent Brain Alterations in a Mouse Model of Hypoxia-Aged Hydrocephalus. Int J Mol Sci. 2021 Sep 9;22(18):9745http://hdl.handle.net/10668/4403Aquaporin-4 (AQP4) is the principal water channel in the brain being expressed in astrocytes and ependymal cells. AQP4 plays an important role in cerebrospinal fluid (CSF) homeostasis, and alterations in its expression have been associated with hydrocephalus. AQP4 contributes to the development of hydrocephalus by hypoxia in aged mice, reproducing such principal characteristics of the disease. Here, we explore whether these alterations associated with the hydrocephalic state are permanent or can be reverted by reexposure to normoxia. Alterations such as ventriculomegaly, elevated intracranial pressure, and cognitive deficits were reversed, whereas deficits in CSF outflow and ventricular distensibility were not recovered, remaining impaired even one month after reestablishment of normoxia. Interestingly, in AQP4-/- mice, the impairment in CSF drainage and ventricular distensibility was completely reverted by re-normoxia, indicating that AQP4 has a structural role in the chronification of those alterations. Finally, we show that aged mice subjected to two hypoxic episodes experience permanent ventriculomegaly. These data reveal that repetitive hypoxic events in aged cerebral tissue promote the permanent alterations involved in hydrocephalic pathophysiology, which are dependent on AQP4 expression.enAtribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/AQP4AstrocytesHypoxiaHydrocephalusCerebrospinal fluidCerebral ventriclesHomeostasisDrainageAcuaporina 4AstrocitosHipoxiaHidrocefaliaLíquido cefalorraquídeoVentrículos cerebralesDrenajeMedical Subject Headings::Health Care::Health Care Quality, Access, and Evaluation::Quality of Health Care::Epidemiologic Factors::Age FactorsMedical Subject Headings::Organisms::Eukaryota::AnimalsMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Carrier Proteins::Membrane Transport Proteins::Ion Channels::Porins::Aquaporins::Aquaporin 4Medical Subject Headings::Chemicals and Drugs::Biological Factors::Biological Markers::Biomarkers, PharmacologicalMedical Subject Headings::Anatomy::Nervous System::Central Nervous System::BrainMedical Subject Headings::Diseases::Animal Diseases::Disease Models, AnimalMedical Subject Headings::Diseases::Nervous System Diseases::Central Nervous System Diseases::Brain Diseases::HydrocephalusMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Clinical Laboratory Techniques::Cytological Techniques::Histocytochemistry::ImmunohistochemistryMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Diagnostic Imaging::Magnetic Resonance ImagingMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::MiceMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::PhenotypeMedical Subject Headings::Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Disease Attributes::Disease SusceptibilityMedical Subject Headings::Anatomy::Nervous System::Neuroglia::AstrocytesMedical Subject Headings::Phenomena and Processes::Physiological Phenomena::Physiological Processes::HomeostasisMedical Subject Headings::Diseases::Nervous System Diseases::Central Nervous System Diseases::Brain Diseases::Intracranial HypertensionMedical Subject Headings::Psychiatry and Psychology::Psychological Phenomena and Processes::Mental Processes::CognitionMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Therapeutics::Drainageresearch article34575909open access10.3390/ijms221897451422-0067PMC8471142