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Physiological impact of CB1 receptor expression by hippocampal GABAergic interneurons

  • Neuroscience
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Abstract

A subset of hippocampal GABAergic neurons, which are cholecystokinin-positive, highly express cannabinoid type 1 (CB1) receptors. Activation of these receptors inhibits GABA release and thereby limits inhibitory control. While genetic deletion of CB1 receptors from GABAergic neurons led to behavioural alterations and neuroinflammatory reactions, it remained unclear whether these changes in the knockout animals were a direct consequence of the enhanced transmitter release or reflected developmental deficits. The hippocampus is vital for the generation of spatial, declarative and working memory. Here, we addressed the question how CB1 receptors in GABAergic neurons influence hippocampal function. Patch clamp and field potential recordings in mice devoid of CB1 receptors in GABAergic neurons revealed an enhanced frequency and faster kinetics of spontaneous inhibitory postsynaptic currents in CA1 pyramidal neurons while tonic inhibition, paired-pulse facilitation and long-term potentiation in the hippocampus were not affected. Evaluation of cognitive functions demonstrated impaired acquisition of spatial memory and deficits in novel object recognition and partner recognition in the knockout mice, while working memory and spatial memory remained intact. The density of GABAergic neurons was also similar in knockout mice and their littermates, which argues against global deficits in hippocampal development. Together, these results suggest that CB1 receptors in GABAergic neurons influence specific aspects of neuronal excitability and hippocampal learning.

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Acknowledgments

We thank Drs. C. Henneberger and S. Künzel for comments on the manuscript and technical support. Grant Sponsors: Deutsche Forschungsgemeinschaft; STE552/3 (to CS), FOR926 SP2, BI-1227/5-1 (to ABG) and FOR926 CP2 (to AZ). European Union; ESF EuroEPINOMICS (to CS). A.Z. is a member of the DFG Cluster of Excellence ImmunoSensation.

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Author notes

  1. Stefan Passlick

    Present address: Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

Authors and Affiliations

  1. Institute of Molecular Psychiatry, Medical Faculty, University of Bonn, Sigmund-Freud Str. 25, 53105, Bonn, Germany

    Önder Albayram, Andras Bilkei-Gorzo & Andreas Zimmer

  2. Institute of Cellular Neurosciences, Medical Faculty, University of Bonn, Sigmund-Freud Str. 25, 53105, Bonn, Germany

    Stefan Passlick & Christian Steinhäuser

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  1. Önder Albayram
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Correspondence to Christian Steinhäuser.

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Önder Albayram and Stefan Passlick contributed equally to this work.

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ESM Fig. 1

Representative microphotographs of GAD67 immunostaining (green) in the CA1 and CA3 regions of the hippocampus of GABA/CB1+/+ and GABA/CB1-/- mice. White arrows indicate the location of GAD67+ cell bodies. Scale bar represents 100 μm (JPG 200 kb)

ESM Fig. 2

Representative microphotographs of PV immunostaining (green) and Hoechst fluorescence (blue) in the CA1 and CA3 regions of the hippocampus of GABA/CB1+/+ and GABA/CB1-/- mice. White arrows indicate the location of PV+ interneurons. Scale bar represents 100 μm (JPG 235 kb)

ESM Fig. 3

Representative microphotographs of CCK immunostaining (green) and Hoechst fluorescence (blue) in the CA1 and CA3 regions of the hippocampus of GABA/CB1+/+ and GABA/CB1-/- mice. White arrows indicate the location of CCK+ interneurons. Scale bar represents 100 μm (JPG 135 kb)

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Albayram, Ö., Passlick, S., Bilkei-Gorzo, A. et al. Physiological impact of CB1 receptor expression by hippocampal GABAergic interneurons. Pflugers Arch - Eur J Physiol 468, 727–737 (2016). https://doi.org/10.1007/s00424-015-1782-5

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