Glia-dependent glutamate spillover triggers repetitive behavior in C. elegans

Glutamate is a major excitatory neurotransmitter. Glial-glutamate transporters serve to clear extracellular glutamate. Impaired clearance may promote glutamate spillover and the induction of extra-synaptic signaling. Although spillover effects on neuronal physiology have been studied extensively, its effects on animal behavior and on corresponding neural-circuit activityare poorly understood. This is mostly due to circuit complexity in the mammalian brain, and to glutamate neurotoxicity, which often promotes neuronal death. The nematode C.elegans, with its simple and well-mapped nervous system connectome, is an attractive model to address this question, as here glutamate is not neurotoxic. We show that loss of the glial glutamate transporter GLT-1 induces glutamate spillover, and drives aberrant repetitive locomotor reversal behavior in C. elegans. In vivo imaging reveals that GLT-1 loss results in uncontrolled oscillatory activation of AVA, a major interneuron governing reversal behavior. This activation is a consequence of oscillatory presynaptic glutamate release onto AVA, and its frequency correlates with the frequency of repetitive behavior. Repetitive glutamate release and reversal behavior require the extra-synaptic metabotropic glutamate receptor MGL-2/mGluR5, expressed in RIM and other neurons presynaptic to AVA. mgl-2 loss blocks glutamate oscillations and repetitive behavior; while optogenetic activation of RIM is sufficient to induce repetitive behavior in glt-1 mutants. Repetitive AVA firing and consequent reversals are promoted by EGL-30/Gaq signaling. Repetitive behaviors are hallmarks of some neuropsychiatric diseases, and murine mGluR5 and astrocyte-expressed GLT1 have been independently implicated in pathological repetitive grooming. Our studies suggest a common mechanism controlling repetitive behaviors by cyclic presynaptic autocrine glutamate signaling.