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Front. Cell. Neurosci. | doi: 10.3389/fncel.2018.00508

Group II metabotropic glutamate receptors mediate presynaptic inhibition of excitatory transmission in pyramidal neurons of the human cerebral cortex

 Marco Bocchio1,  Istvan Lukacs1, Richard Stacey2, Puneet Plaha2, Vasileios Apostolopoulos2, Laurent Livermore2, Arjune Sen3, Olaf Ansorge3, Martin J. Gillies3,  Peter Somogyi1 and  Marco Capogna4*
  • 1Department of Pharmacology, University of Oxford, United Kingdom
  • 2Oxford University Hospitals NHS Trust, United Kingdom
  • 3Nuffield Department of Clinical Neurosciences, Medical Sciences Division, University of Oxford, United Kingdom
  • 4Aarhus University, Denmark

Group II metabotropic glutamate receptor (mGluR) ligands are potential novel drugs for neurological and psychiatric disorders, but little is known about the effects of these compounds at synapses of the human cerebral cortex. Investigating the effects of neuropsychiatric drugs in human brain tissue with preserved synaptic circuits might accelerate the development of more potent and selective pharmacological treatments. We have studied the effects of group II mGluR activation on excitatory synaptic transmission recorded from pyramidal neurons of cortical layers 2-3 in acute slices derived from surgically removed cortical tissue of people with epilepsy or tumours. The application of a selective group II mGluR agonist, LY354740 (0.1-1 M) inhibited the amplitude and frequency of action potential-dependent spontaneous excitatory postsynaptic currents (sEPSCs). This effect was prevented by the application of a group II/III mGluR antagonist, CPPG (0.1 M). Furthermore, LY354740 inhibited the frequency, but not the amplitude, of action potential-independent miniature EPSCs (mEPSCs) recorded in pyramidal neurons. Finally, LY354740 did slightly reduce cells’ input resistance without altering the holding current of the neurons recorded in voltage clamp at -90 mV. Our results suggest that group II mGluRs are mainly auto-receptors that inhibit the release of glutamate onto pyramidal neurons in layers 2-3 in the human cerebral cortex, thereby regulating network excitability. We have demonstrated the effect of a group II mGluR ligand at human cortical synapses, revealing mechanisms by which these drugs could exert pro-cognitive effects and treat human neuropsychiatric disorders.

Keywords: Presynaptic receptor, glutamatergic, EPSC (excitatory postsynaptic current), cognitive enhancement, acute slices of human cortex

Received: 29 Oct 2018; Accepted: 07 Dec 2018.

Edited by:

Enrico Cherubini, Scuola Internazionale Superiore di Studi Avanzati (SISSA), Italy

Reviewed by:

Annalisa Scimemi, University at Albany, United States
Huib Mansvelder, VU University Amsterdam, Netherlands  

Copyright: © 2018 Bocchio, Lukacs, Stacey, Plaha, Apostolopoulos, Livermore, Sen, Ansorge, Gillies, Somogyi and Capogna. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Marco Capogna, Aarhus University, Aarhus, 8000, Central Denmark Region, Denmark, marco.capogna@biomed.au.dk