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Front. Cell. Neurosci. | doi: 10.3389/fncel.2018.00449

A Light-controlled Allosteric Modulator Unveils a Role for mGlu4 Receptors During Early Stages of Ischemia in the Rodent Cerebellar Cortex

  • 1UMR9197 Institut des Neurosciences Paris Saclay (Neuro-PSI), France
  • 2Instituto de Química Avanzada de Cataluña (IQAC), Spain
  • 3Universitat de Vic - Universitat Central de Catalunya, Spain

Metabotropic glutamate receptors (mGlus) are G Protein coupled-receptors that modulate synaptic transmission and plasticity in the central nervous system. Some act as autoreceptors to control neurotransmitter release at excitatory synapses and have become attractive targets for drug therapy to treat certain neurological disorders. However, the high degree of sequence conservation around the glutamate binding site makes the development of subtype-specific orthosteric ligands difficult to achieve. This problem can be circumvented by designing molecules that target specific less well conserved allosteric sites. One such allosteric drug, the photo-switchable compound OptoGluNAM4.1, has been recently employed to reversibly inhibit the activity of metabotropic glutamate 4 (mGlu4) receptors in cell cultures and in vivo. We studied OptoGluNAM4.1 as a negative modulator of neurotransmission in rodent cerebellar slices at the parallel fiber - Purkinje cell synapse. Our data show that OptoGluNAM4.1 antagonizes pharmacological activation of mGlu4 receptors in a fully reversible and photo-controllable manner. In addition, for the first time, this new allosteric modulator allowed us to demonstrate that, in brain slices from the rodent cerebellar cortex, mGlu4 receptors are endogenously activated in excitotoxic conditions, such as the early phases of simulated cerebellar ischemia, which is associated with elevated levels of extracellular glutamate. These findings support OptoGluNAM4.1 as a promising new tool for unraveling the role of mGlu4 receptors in the central nervous system in physio-pathological conditions.

Keywords: Presynaptic metabotropic glutamate receptor 4, allosteric modulation, photopharmacology, Cerebellar Cortex, Oxygen glucose deprivation (OGD)

Received: 30 Aug 2018; Accepted: 07 Nov 2018.

Edited by:

Philippe Isope, Centre national de la recherche scientifique (CNRS), France

Reviewed by:

Thomas Launey, RIKEN Brain Science Institute (BSI), Japan
Francesca Prestori, University of Pavia, Italy  

Copyright: © 2018 Bossi, Helleringer, Galante, Monlleo, Trapero, Rovira, Daniel, Llebaria and McLean. 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: PhD. Heather McLean, UMR9197 Institut des Neurosciences Paris Saclay (Neuro-PSI), Gif-sur-Yvette, France, heather.mclean@u-psud.fr