Water for thought: is there a role for aquaporin channels in delirium?

C. G. Jung believed that water was a symbol for the unconscious mind, the background from where our conscious thoughts emerge, and also the sea where they melt into the dream-like state of primary processes (1). Water comprises about 80% of the brain volume and water homeostasis is inextricably coupled to the CNS function. In this regard, neuroscience describes an inverse relationship between the intensity of the neuropil function and the amount of water it contains. For example, during high neuronal activity (such as information processing), water is transported away from the neuropil, shrinking the extracellular matrix (ECM). Conversely, during times of lower brain activity (such as during sleep), water is shifted back to the neuropil, expanding the ECM (2, 3). The movement of water in and out of the neuropil occurs with the help of the glymphatic system via special molecular pumps, aquaporin water channels (AQP 4) located in astrocyte end-feet. Water circulation is enabled by the exchange between the cerebrospinal fluid (CSF) and interstitial fluid (ISF). The pressure gradient for this exchange is probably provided by pericytes’ contraction and arterial pulsations along with the suction, pump-like action of AQP 4 channels (4–6). This movement of water in and out of the neuropil enables both, clearance of molecular waste and volume transmission (VT) of chemical signals (7). Conversely, delayed water movement (glymphatic stasis) may predispose to the accumulation of misfolded proteins (4) and ultimately to neuroinflammation (8). The relationship between water and delirium is complex. Both, brain edema and dehydration may predispose to delirium (9). Up-regulation of AQP 4 water channels seems to occur in both situations. In fact, a biphasic up-regulation was described in edema build-up and the resolution phase (10). Interestingly, AQP 4 receptors seem to be the common denominator between the neuropil water movement and neuroinflammation (10). Moreover, animal studies demonstrated that peripheral dehydration triggers central up-regulation of AQP 4 receptors (11–13). This in turn causes swelling and priming of astrocytes and microglia, predisposing to neuroinflammation (14). According to a recent study, two key factors, systemic inflammation and central cholinergic impairment must interact in order to produce delirium (15). The goal of this article is not to discuss VT or the relationship between AQP 4 channels and inflammation since extensive literature exists on these subjects. Instead, we attempt to answer three questions: Can an inefficient glymphatic clearance lead to impairment of central cholinergic transmission? Does glymphatic stasis contribute to microglia and astrocytes’ priming, the precursor of neuroinflammation? Do aquaporin blockers have a place in delirium? We hypothesize that failure of glymphatic clearance leads to impairment of acetylcholine volume transmission (AChVT), contributing to impaired arousal, attention, memory, and sleep as seen in delirium. We hypothesize further, that glymphatic failure is pro-inflammatory in nature, leading to up-regulation of AQP 4 channels, which in turn trigger astrocyte swelling and gliosis with the end result being microglial and astrocytic priming. The above phenomena may reconcile two theories of delirium: central cholinergic deficit and neuroinflammation.