Phasic and Tonic mGlu7 Receptor Activity Modulates the Thalamocortical Network

Front Neural Circuits. 2016 Apr 25;10:31. doi: 10.3389/fncir.2016.00031. eCollection 2016.

Abstract

Mutation of the metabotropic glutamate receptor type 7 (mGlu7) induces absence-like epileptic seizures, but its precise role in the somatosensory thalamocortical network remains unknown. By combining electrophysiological recordings, optogenetics, and pharmacology, we dissected the contribution of the mGlu7 receptor at mouse thalamic synapses. We found that mGlu7 is functionally expressed at both glutamatergic and GABAergic synapses, where it can inhibit neurotransmission and regulate short-term plasticity. These effects depend on the PDZ-ligand of the receptor, as they are lost in mutant mice. Interestingly, the very low affinity of mGlu7 receptors for glutamate raises the question of how it can be activated, namely at GABAergic synapses and in basal conditions. Inactivation of the receptor activity with the mGlu7 negative allosteric modulator (NAM), ADX71743, enhances thalamic synaptic transmission. In vivo administration of the NAM induces a lethargic state with spindle and/or spike-and-wave discharges accompanied by a behavioral arrest typical of absence epileptic seizures. This provides evidence for mGlu7 receptor-mediated tonic modulation of a physiological function in vivo preventing synchronous and potentially pathological oscillations.

Keywords: EEG; epilepsy; glutamate; short-term plasticity; thalamic network.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzoxazoles / chemistry
  • Benzoxazoles / pharmacology
  • Cerebral Cortex / cytology*
  • Cerebral Cortex / physiology
  • Channelrhodopsins
  • Excitatory Amino Acid Agents / pharmacology
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / genetics
  • GABA Agents / pharmacology
  • GTP-Binding Protein alpha Subunits, Gq-G11 / genetics
  • GTP-Binding Protein alpha Subunits, Gq-G11 / metabolism
  • HEK293 Cells
  • Humans
  • In Vitro Techniques
  • Membrane Potentials / drug effects
  • Membrane Potentials / genetics
  • Mice
  • Mice, Transgenic
  • Mutation / genetics
  • Neural Pathways / physiology*
  • Neurons / drug effects
  • Neurons / physiology
  • Post-Synaptic Density / drug effects
  • Post-Synaptic Density / genetics
  • Receptors, GABA-A / physiology
  • Receptors, Metabotropic Glutamate / genetics
  • Receptors, Metabotropic Glutamate / metabolism*
  • Synaptic Potentials / drug effects
  • Synaptic Potentials / genetics
  • Thalamus / physiology*

Substances

  • ADX71743
  • Benzoxazoles
  • Channelrhodopsins
  • Excitatory Amino Acid Agents
  • GABA Agents
  • Receptors, GABA-A
  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor 7
  • GTP-Binding Protein alpha Subunits, Gq-G11