Ion concentrations in cerebrospinal fluid in wakefulness, sleep and sleep deprivation in healthy humans.

Sleep is controlled by a circadian rhythmicity, via a reduction of arousal-promoting neuromodulatory activity, and by accumulation of somnogenic factors in the interstitial fluid of the brain. Recent experiments in mice suggest that a reduced neuronal excitability caused by a reduced concentration of potassium in the brain, concomitant with an increased concentration of calcium and magnesium, constitutes an important mediator of sleep. In the present study, we examined whether such changes in ion concentrations could be detected in the cerebrospinal fluid of healthy humans. Each subject underwent cerebrospinal fluid collection at three occasions in a randomized order: at 15:00 hours-17:00 hours during waking, at 06:00 hours-07:00 hours immediately following 1 night of sleep, and at 06:00 hours-07:00 hours following 1 night of sleep deprivation. When compared with wakefulness, both sleep and sleep deprivation produced the same effect of a small (0.1 mm, about 3%), but robust and highly significant, reduction in potassium concentration. Calcium and magnesium concentrations were unchanged. Our results support a circadian modulation of neuronal excitability in the brain mediated via changes of the interstitial potassium concentration.

Human cerebrospinal fluid promotes spontaneous gamma oscillations in the hippocampus in vitro.

Gamma oscillations (30-80 Hz) are fast network activity patterns frequently linked to cognition. They are commonly studied in hippocampal brain slices in vitro, where they can be evoked via pharmacological activation of various receptor families. One limitation of this approach is that neuronal activity is studied in a highly artificial extracellular fluid environment, as provided by artificial cerebrospinal fluid (aCSF). Here, we examine the influence of human cerebrospinal fluid (hCSF) on kainate-evoked and spontaneous gamma oscillations in mouse hippocampus. We show that hCSF, as compared to aCSF of matched electrolyte and glucose composition, increases the power of kainate-evoked gamma oscillations and induces spontaneous gamma activity in areas CA3 and CA1 that is reversed by washout. Bath application of atropine entirely abolished hCSF-induced gamma oscillations, indicating critical contribution from muscarinic acetylcholine receptor-mediated signaling. In separate whole-cell patch clamp recordings from rat hippocampus, hCSF increased theta resonance frequency and strength in pyramidal cells along with enhancement of h-current (Ih ) amplitude. We found no evidence of intrinsic gamma frequency resonance at baseline (aCSF) among fast-spiking interneurons, and this was not altered by hCSF. However, hCSF increased the excitability of fast-spiking interneurons, which likely contributed to gamma rhythmogenesis. Our findings show that hCSF promotes network gamma oscillations in the hippocampus in vitro and suggest that neuromodulators distributed in CSF could have significant influence on neuronal network activity in vivo.

Ionized calcium in human cerebrospinal fluid and its influence on intrinsic and synaptic excitability of hippocampal pyramidal neurons in the rat.

It is well-known that the extracellular concentration of calcium affects neuronal excitability and synaptic transmission. Less is known about the physiological concentration of extracellular calcium in the brain. In electrophysiological brain slice experiments, the artificial cerebrospinal fluid traditionally contains relatively high concentrations of calcium (2-4 mM) to support synaptic transmission and suppress neuronal excitability. Using an ion-selective electrode, we determined the fraction of ionized calcium in healthy human cerebrospinal fluid to 1.0 mM of a total concentration of 1.2 mM (86%). Using patch-clamp and extracellular recordings in the CA1 region in acute slices of rat hippocampus, we then compared the effects of this physiological concentration of calcium with the commonly used 2 mM on neuronal excitability, synaptic transmission, and long-term potentiation (LTP) to examine the magnitude of changes in this range of extracellular calcium. Increasing the total extracellular calcium concentration from 1.2 to 2 mM decreased spontaneous action potential firing, induced a depolarization of the threshold, and increased the rate of both de- and repolarization of the action potential. Evoked synaptic transmission was approximately doubled, with a balanced effect between inhibition and excitation. In 1.2 mM calcium high-frequency stimulation did not result in any LTP, whereas a prominent LTP was observed at 2 or 4 mM calcium. Surprisingly, this inability to induce LTP persisted during blockade of GABAergic inhibition. In conclusion, an increase from the physiological 1.2 mM to 2 mM calcium in the artificial cerebrospinal fluid has striking effects on neuronal excitability, synaptic transmission, and the induction of LTP. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/. Read the Editorial Highlight for this article on page 435.