Several neurological disorders are associated with disrupted dopamine (DA) signaling including Parkinson's disease, schizophrenia and addiction. In C. elegans, an inability to clear synaptic DA results in swimming induced paralysis (Swip). In a screen for animals that display DA-dependent Swip, we identified two mutants that support DA-dependent Swip,
vt29 and
vt33, and that lie within a previously undescribed gene F53B1.6, now named
swip-10. Sequence analysis revealed highly conserved mouse and human orthologs, Mblac1 and MBLAC1 respectively, named for the presence of metallo-b lactamase domains. Swip-10 promoter:GFP fusion constructs yielded expression in C. elegans glial cells in vivo. Consistent with this localization, rescue of Swip was achieved by expressing
swip-10 under either its own promoter or the
ptr-10 glial promoter. In the mammalian brain, glial cells regulate DA neurons and DA-modulated circuits by clearing extracellular glutamate via expression of high affinity glutamate transporters. Immunocytochemical studies reveal high levels of Mblac1 expression in the mouse brain in areas associated with glutamatergic control of emotional and reward behaviors including the prefrontal cortex, hippocampus, nucleus accumbens, habenula and amygdala. In keeping with a role of
swip-10 in regulating glutamate-dependent DA neuron excitation, we found that mutation of multiple GLTs generates DA-dependent Swip and that
swip-10 and
glt-4 interact genetically to trigger Swip. Additionally, loss of the glutamate receptors,
glr-4,
glr-6 and
mgl-1, individually and in combination diminished the Swip of
swip-10. Our results suggest that
swip-10 is a novel regulator of extracellular glutamate via altered glutamate transport. We hypothesize that knockout of
swip-10 elevates tonic extracellular glutamate, increases excitation of DA neurons, and increases DA release. Further analysis of
swip-10 and its mammalian orthologs may lead to novel insights into brain disorders linked to altered glutamate signaling, including those for which perturbed glutamate-control of DA signaling has been documented. F31MH09312 to JAH and R01MH095044 to RDB.