Neural circuits control animal behavior, and their dysfunction promotes neurological diseases manifesting aberrant behaviors. Neural circuits are tightly associated with astroglial processes, yet glial roles in animal behavior are not well understood. C. elegans has a compact nervous system driving a limited and well-characterized behavioral repertoire. C. elegans glia are not essential for neuron viability, making this animal a useful setting for investigating glial influences on circuits and behavior. We have characterized roles of the brain-associated C. elegans CEPsh glia in animal locomotion. We demonstrate that, like astrocytes, CEPsh glia infiltrate the brain neuropil and abut glutamatergic synapses. Postembryonic ablation of CEPsh glia results in foraging defects, including an increased reversal rate. CEPsh glia transcriptome analysis reveals similarities to astrocytes, including expression of the glial glutamate transporter, glt-1. Behavior studies reveal that glt-1 mutants, unlike wild-type animals, have increased reversal frequency, as well as repetitive reversal bouts. AVA neurons control reversal initiation, and our in vivo measurements of synaptic glutamate adjacent to AVA reveal roles for glial GLT-1 in rapid glutamate clearance. Inappropriate clearance leads to high-frequencies oscillations in synaptic glutamate and AVA activation. We show that these oscillations are mediated by the presynaptic metabotropic glutamate receptor mgl-2/mGluR5, and that mutations in mgl-2 suppress glt-1-mediated repetitive reversals. Loss of murine astrocyte-expressed GLT1 has been shown to produce repetitive grooming, and inhibition of murine mGluR5 ameliorates repetitive behavior in an Obsessive Compulsive Disease (OCD) model. Our studies, therefore, suggest conserved roles for glutamate clearance by glia in controlling repetitive behavior, a feature of some human neuropsychiatric disorders.

Authors: Katz, Menachem, Corson, Francis, Singhal, Anupriya, Keil, Wolfgang, Bae, Andrea, Lu, Yun, Liang, Yupu, Shaham, Shai

Affiliations:
- Center for Studies in Physics and Biology, The Rockefeller University, New York, NY
- Laboratoire de Physique Statistique, Ecole Normale Superieure, Paris, France
- Laboratory of Developmental Genetics, The Rockefeller University, New York, NY
- Research Bioinformatics, The Rockefeller University, New York, NY