Brain Interstitial Matrix Hydration Inversely Correlates with Neuronal Excytability

Abstract

Interstitial flux of cerebrospinal fluid (CSF) mediates optimal transfer, clearance, and exchange of molecules in the brain. To determine whether disturbances during dehydration or edema lead to neuronal dysfunction, we quantified hydration in the brains of mice subjected to mild water deprivation and measured neuronal excitability in the dehydrated and rehydrated hippocampus. Specifically, we titrated water activity ex vivo using artificial CSF solutions of nonpenetrating inert polymers adjusted to give colloidosmotic pressures in the 0-200 mmHg range. Compared to nondeprived controls, the brains of water-deprived mice had hydration potentials of 94.5 ± 5.4 and 103.8 ± 3.5 mmHg after 12 and 24 hours, respectively, corresponding to 23 and 28 mmHg increases in potential, or 20% and 27% decreases in hydration. The brain-matrix hydraulic conductance, 0.051 ± 0.0019 µl/min/g/mmHg, did not change significantly (n = 6 hydrated/dehydrated pairs). The field excitatory postsynaptic potentials (fEPSP) in the hippocampus, adjusted to hydrations 25 and 125 mmHg below controls, increased 47% and 66%, respectively, but did not change at hydrations up to 75 mmHg above control. In addition, the level of phosphorylated CREB (cAMP response-binding protein), a key mediator of neuronal excitatory pathways, increased in dehydrated hippocampus after subthreshold stimulation.These results show that brain dehydration levels comparable to those measured following short-term water deprivation in mice increase neuronal excitability. Neurons appear very sensitive to water-activity changes, suggesting local dehydration in the interstitial matrix contributes to the cognitive deficits seen in dehydrated humans. As a plausible mechanism, we suggest that lower water activity in dehydrated brains increases the effective concentration of all solutes, modifying the timing, diffusivities, and probabilities of neurotransmitters binding to their cognate receptors.