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Activation of type-1 cannabinoid receptor shifts the balance between excitation and inhibition towards excitation in layer II/III pyramidal neurons of the rat prelimbic cortex

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Abstract

Activation of the endocannabinoid (eCB) system by exogenous cannabinoids (drug abuse) can alter the physiology of the brain circuits involved in higher-order cognitive functions such as the medial prefrontal cortex (mPFC). A proper balance between excitation and inhibition (E/I balance) is critical for neuronal network oscillations underlying cognitive functions. Since type-1 cannabinoid receptors (CB1Rs), expressed in many brain areas including the mPFC, can modulate excitatory and inhibitory neurotransmission, we aimed to determine whether CB1R activation results in modifications of the E/I balance. We first confirm the presence of functional presynaptic CB1Rs that can modulate both excitatory and inhibitory inputs to layer II/III pyramidal neurons of the prelimbic (PL) area of the mPFC. By decomposing the synaptic response evoked by layer I stimulation into its excitatory and inhibitory components, we show that in vitro CB1R activation with the cannabinoid receptor agonists WIN55,212-2 (WIN) and CP-55940 (CP) modulates the balance between excitation and inhibition (E/I balance) of layer II/III pyramidal neurons. This treatment caused a significant shift of the E/I balance towards excitation, from 18/82 % to 25/75 % (WIN) and from 17/83 to 30/70 % (CP). Finally, when animals were injected with a cannabinoid receptor agonist, we observed a shift of the E/I balance (measured in vitro) towards excitation 1 h after WIN (24/76 %) or after CP injection (30/70 %) when compared to vehicle-injected animals (18/82 %). This modulation of the E/I balance by CB1Rs may thus be fundamental in the regulation of local PL cortical network excitability and could be the mechanism through which excessive CB1R activation (cannabis abuse) affects cognitive functions.

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Acknowledgements

We thank Willem van Aken for help with the immunohistochemical experiments and Dr. J.A. Gorter for his comments on the manuscript. Author contributions are as follows: conception and design: F.S.B., T.R.W. and P.C.; collection of data: F.S.B., Q.S., K.H. and P.C.; analysis and interpretation of data: F.S.B., T.R.W., W.J.W. and P.C.; drafting and revision of the article: F.S.B., T.R.W. and P.C; and critical revision of the manuscript: T.V., C.G.K. and W.J.W. All authors approved the final version of the manuscript. This study was supported by Dutch Top Institute Pharma Grant T5-107-1.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, Science Park 904, 1098 XH, Amsterdam, Netherlands

    Femke S. den Boon, Taco R. Werkman, Qiluan Schaafsma-Zhao, Kas Houthuijs, Chris G. Kruse, Wytse J. Wadman & Pascal Chameau

  2. CNRS-UMR 7637, Brain Plasticity Unit, ESPCI ParisTech, 10 rue Vauquelin, 75005, Paris, France

    Tania Vitalis

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  1. Femke S. den Boon
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Correspondence to Taco R. Werkman.

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den Boon, F.S., Werkman, T.R., Schaafsma-Zhao, Q. et al. Activation of type-1 cannabinoid receptor shifts the balance between excitation and inhibition towards excitation in layer II/III pyramidal neurons of the rat prelimbic cortex. Pflugers Arch - Eur J Physiol 467, 1551–1564 (2015). https://doi.org/10.1007/s00424-014-1586-z

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