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.
Highlights
Glutamate is a major excitatory neurotransmitter, and impaired glutamate clearance following synaptic release promotes spillover, inducing extra-synaptic signaling
This is in line with the developmental origins of these cells: C. elegans CEPsh glia, and mammalian neurons, astrocytes, and oligodendrocytes, are all ectodermally derived, whereas microglia and endothelial cells are of mesodermal origin[16]
Rank- b ordering mRNAs, according to fold-enrichment (FE) within a cell type, reveals that the more highly enriched a gene is in CEPsh glia, the more likely is its ortholog to be enriched in murine astrocytes, but not in oligodendrocytes
Summary
Glutamate is a major excitatory neurotransmitter, and impaired glutamate clearance following synaptic release promotes spillover, inducing extra-synaptic signaling. In vivo measurements of extracellular glutamate dynamics near postsynaptic sites of the interneuron AVA, a major regulator of reversal behavior, show that GLT-1 is required to prevent oscillations in synaptic glutamate release, and consequent oscillations in AVA activity, which correlate with repetitive reversal events in frequency. Both oscillations in AVA neuron activity and repetitive behavior are mediated by activation of the metabotropic glutamate receptor MGL-2/mGluR5 in glutamatergic interneurons presynaptic to AVA.
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