Two Mechanisms That Raise Free Intracellular Calcium in Rat Hippocampal Neurons During Hypoosmotic and Low NaCl Treatment

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Abstract
Previous studies have shown that exposing hippocampal slices to low osmolarity (πo) or to low extracellular NaCl concentration ([NaCl]o) enhances synaptic transmission and also causes interstitial calcium ([Ca2+]o) to decrease. Reduction of [Ca2+]osuggests cellular uptake and could explain the potentiation of synaptic transmission. We measured intracellular calcium activity ([Ca2+]i) using fluorescent indicator dyes. In CA1 hippocampal pyramidal neurons in tissue slices, lowering πoby ∼70 mOsm caused “resting” [Ca2+]ias well as synaptically or directly stimulated transient increases of calcium activity (Δ[Ca2+]i) to transiently decrease and then to increase. In dissociated cells, lowering πoby ∼70 mOsm caused [Ca2+]ito almost double on average from 83 to 155 nM. The increase of [Ca2+]iwas not significantly correlated with hypotonic cell swelling. Isoosmotic (mannitol- or sucrose-substituted) lowering of [NaCl]o, which did not cause cell swelling, also raised [Ca2+]i. Substituting NaCl with choline-Cl or Na-methyl-sulfate did not affect [Ca2+]i. In neurons bathed in calcium-free medium, lowering πocaused a milder increase of [Ca2+]i, which was correlated with cell swelling, but in the absence of external Ca2+, isotonic lowering of [NaCl]otriggered only a brief, transient response. We conclude that decrease of extracellular ionic strength (i.e., in both low πoand low [NaCl]o) causes a net influx of Ca2+from the extracellular medium whereas cell swelling, or the increase in membrane tension, is a signal for the release of Ca2+from intracellular stores.