Glutamate spillover in C. elegans triggers repetitive behavior through presynaptic activation of MGL-2/mGluR5

Nat Commun. 2019 Apr 23;10(1):1882. doi: 10.1038/s41467-019-09581-4.

Abstract

Glutamate is a major excitatory neurotransmitter, and impaired glutamate clearance following synaptic release promotes spillover, inducing extra-synaptic signaling. The effects of glutamate spillover on animal behavior and its neural correlates are poorly understood. We developed a glutamate spillover model in Caenorhabditis elegans by inactivating the conserved glial glutamate transporter GLT-1. GLT-1 loss drives aberrant repetitive locomotory reversal behavior through uncontrolled oscillatory release of glutamate onto AVA, a major interneuron governing reversals. Repetitive glutamate release and reversal behavior require the glutamate receptor MGL-2/mGluR5, expressed in RIM and other interneurons presynaptic to AVA. mgl-2 loss blocks oscillations and repetitive behavior; while RIM activation is sufficient to induce repetitive reversals in glt-1 mutants. Repetitive AVA firing and reversals require EGL-30/Gαq, an mGluR5 effector. Our studies reveal that cyclic autocrine presynaptic activation drives repetitive reversals following glutamate spillover. That mammalian GLT1 and mGluR5 are implicated in pathological motor repetition suggests a common mechanism controlling repetitive behaviors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Behavior, Animal / physiology*
  • Caenorhabditis elegans / physiology*
  • Caenorhabditis elegans Proteins / metabolism*
  • Datasets as Topic
  • Excitatory Amino Acid Transporter 2 / metabolism
  • Gene Expression Profiling
  • Glutamic Acid / metabolism*
  • Interneurons / metabolism
  • Locomotion / physiology
  • Models, Animal
  • Presynaptic Terminals / physiology*
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate / genetics
  • Receptors, Metabotropic Glutamate / metabolism*

Substances

  • Caenorhabditis elegans Proteins
  • Excitatory Amino Acid Transporter 2
  • Grm5 protein, mouse
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate
  • mgl-2 protein, C elegans
  • Glutamic Acid