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Abstract
Aquaporin-4 (AQP4) is the major water channel in the CNS. Its expression at fluid-tissue
barriers (blood-brain and brain-cerebrospinal fluid barriers) throughout the brain
and spinal cord suggests a role in water transport under normal and pathological conditions.
Phenotype studies of transgenic mice lacking AQP4 have provided evidence for a role
of AQP4 in cerebral water balance and neural signal transduction. Primary cultures
of astrocytes from AQP4-null mice have greatly reduced osmotic water permeability
compared with wild-type astrocytes, indicating that AQP4 is the principal water channel
in these cells. AQP4-null mice have reduced brain swelling and improved neurological
outcome following water intoxication and focal cerebral ischemia, establishing a role
of AQP4 in the development of cytotoxic (cellular) cerebral edema. In contrast, brain
swelling and clinical outcome are worse in AQP4-null mice in models of vasogenic (fluid
leak) edema caused by freeze-injury and brain tumor, probably due to impaired AQP4-dependent
brain water clearance. AQP4-null mice also have markedly reduced acoustic brainstem
response potentials and significantly increased seizure threshold in response to chemical
convulsants, implicating AQP4 in modulation of neural signal transduction. Pharmacological
modulation of AQP4 function may thus provide a novel therapeutic strategy for the
treatment of stroke, tumor-associated edema, epilepsy, traumatic brain injury, and
other disorders of the CNS associated with altered brain water balance.