Dehydration Impairs Synaptic Plasticity by Interfering with Late‐Phase Long‐Term Potentiation (L‐LTP)

Dehydration impairs cognitive function. To explore the possible mechanisms, we dehydrated mouse brain tissue and measured LTP, the best understood cellular process of synaptic plasticity that underlies learning and memory in vertebrates. We determined physiologic hydration by titrating water activity in mouse brain explants. Specifically, we immersed the 60–90‐mg explants in baths of artificial cerebrospinal fluid (ACSF) equilibrated at room temperature in which inert, non‐penetrating polymer polyethylene glycol 8000 was dissolved to attain colloidosmotic pressures of 0 mmHg (in control ACSF), 54 mmHg, 101 mmHg, and 196 mmHg. We then calculated the parameters reflecting brain hydration, including hydration potential and hydraulic conductance, from initial flow rates determined gravimetrically. To explore the effect of dehydration on synaptic plasticity, hippocampus slices were equilibrated for 30 min at the above pressures prior to recording field excitatory postsynaptic potentials (fEPSP). Parameters for basal synaptic transmission were derived from input‐output tracings following incremental stimuli. In a separate set of slices, L‐LTP was induced by spacing four 100‐Hz trains 5‐min apart and recording the results for 3 h. Water activity titrations were conducted at room temperature and LTP at 32 °C. All experiments were reproduced in at least 6 mice; results are presented as means and standard errors. Fluid transferred either to or from the brain explants, depending on the bath pressure. Initial fluid transfer rates—3.486 ± 0.1919, 0.08950 ± 0.3907, −1.820 ± 1.258 and −4.248 ± 2.338 μl/min/g— increased linearly ( r 2 > 0.9, by linear regression analyses ) with nominal bath pressures of 0, 54, 101, and 196 mmHg, respectively. The hydraulic conductance , calculated from the slope of the fitted regression lines, was 0.051 ± 0.0019 μl/min/g/mmHg, and the hydration potential , calculated from the pressure at initial rate = 0, was 56.44 ± 4.96 mmHg. In slices equilibrated at near this physiologic hydration potential, basal synaptic transmission resembled that of the slices in control ACSF. However, dehydrating the slices by increasing the colloid osmotic pressure increased basal synaptic transmission, indicating neuronal hyper‐excitability. Similarly, L‐LTP induced at the 54 mmHg level did not differ from that in controls, but progressive dehydration impaired its induction. Induction was completely abolished at a nominal pressure of 196 mmHg. The surprisingly high hydration potential measured in the explanted brain tissue indicates lower water activity in the brain interstitial matrix than in cerebrospinal fluid (CSF) and reflects competition for water in the crowded brain microenvironment. As a notable consequence, neuronal excitability is highly sensitive to changes in water activity. Our findings predict that local dehydration affects cognitive function and impairs synaptic plasticity by preventing L‐LTP induction.