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J Physiol. 2016 Feb 15;594(4):937-52. doi: 10.1113/JP271553. Epub 2016 Jan 18.

Neuromodulation of fast-spiking and non-fast-spiking hippocampal CA1 interneurons by human cerebrospinal fluid.

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Department of Physiology, Institute of Neuroscience and Physiology, University of Gothenburg, 405 30 Gothenburg, Sweden.
Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, University of Gothenburg, 413 45 Gothenburg, Sweden.
Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg, 431 80 Molndal, Sweden.
Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.



How the brain extracellular fluid influences the activity of GABAergic interneurons in vivo is not known. This issue is examined in the hippocampal brain slice by comparing GABAergic interneuron activity in human versus artificial cerebrospinal fluid. Human cerebrospinal fluid (hCSF) substantially increases the excitability of fast-spiking and non-fast-spiking CA1 interneurons. CA1 pyramidal cells are even more strongly excited by hCSF. The tonic excitation of pyramidal cells, in combination with an increased responsiveness of interneurons to excitatory input, is likely to promote the generation of synchronized network activity in the hippocampus.


GABAergic interneurons intricately regulate the activity of hippocampal and neocortical networks. Their function in vivo is likely to be tuned by neuromodulatory substances in the brain extracellular fluid. However, in vitro investigations of GABAergic interneuron function do not account for such effects, as neurons are kept in artificial extracellular fluid. To examine the neuromodulatory influence of brain extracellular fluid on GABAergic activity, we recorded from fast-spiking and non-fast-spiking CA1 interneurons, as well as from pyramidal cells, in the presence of human cerebrospinal fluid (hCSF), using a matched artificial cerebrospinal fluid (aCSF) as control. We found that hCSF increased the frequency of spontaneous firing more than twofold in the two groups of interneurons, and more than fourfold in CA1 pyramidal cells. hCSF did not affect the resting membrane potential of CA1 interneurons but caused depolarization in pyramidal cells. The increased excitability of interneurons and pyramidal cells was accompanied by reductions in after-hyperpolarization amplitudes and a left-shift in the frequency-current relationships. Our results suggest that ambient concentrations of neuromodulators in the brain extracellular fluid powerfully influence the excitability of neuronal networks.

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