Precise coordination between L-glutamate (GLU) and dopamine (DA) neurotransmission drives many complex behaviors such as locomotion, reward and learning. Perturbations in the normal interactions of these neurotransmitters are believed to drive an array of brain disorders including addiction, schizophrenia and Parkinson’s disease. Using the genetic model system C. elegans, we identified a conserved, glial-expressed gene, swip-10, that acts as a glutamatergic regulator of DA signaling. We have shown that mutations in swip-10 lead to increased DA neuron excitability, elevated rates of DA vesicle fusion and the hyperdopaminerigic phenotype, Swimming induced paralysis (Swip). Glial-specific expression of wildtype swip-10 restores normal DA neuron excitability as well as normal swimming behavior. Moreover, pre- and post-synaptic genetic disruptions of GLU signaling suppress Swip. Based on these studies, and well known findings that vertebrate glia regulate neuronal excitation via tight buffering of extracellular GLU levels, we hypothesize that swip-10 functions in glial pathways that normally limit extracellular GLU availability and that loss of swip-10 expression drives GLU-dependent elevations in DA neuron excitation and DA release. Elevated extracellular GLU availability in the mammalian brain can alter neural morphology and ultimately lead to excitotoxic cell death. We find that swip-10 DA neurons exhibit significant dystrophic processes, shrunken and/or missing cell soma, which are suggestive of progressive stages of excitotoxiticity. Glial-specific expression of wildtype swip-10 restores normal DA neuron morphology. Moreover, genetic disruption of GLU release by loss of the vesicular GLU transporter type 3 (vglu-3), suppresses the DA neuron morphology changes of swip-10 mutants. Lastly, post-synaptic genetic disruption of GLU signaling through loss of select GLU receptors also suppresses swip-10 DA neuron morphology alterations. Our studies indicate that whereas swip-10 mutants exhibit hyperdopaminergia linked to the Swip phenotype, they also appear to be undergoing GLU-dependent morphological changes, consistent with an excitotoxic insult. Ongoing genetic, biochemical and pharmacological studies seek to further elaborate the glial pathways through which swip-10 regulates extracellular GLU homeostasis and DA neuron morphology.
Supported by NIH Award MH095044 (R.D.B.).