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J. Biol. Chem., Vol. 282, Issue 47, 34412-34419, November 23, 2007

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Caenorhabditis elegans Glutamate Transporters Influence Synaptic Function and Behavior at Sites Distant from the Synapse^*

Itzhak Mano¹, Sarah Straud², and Monica Driscoll³

From the Department of Molecular Biology and Biochemistry, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854 and the Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390

To ensure precise neurotransmission and prevent neurotoxic accumulation, L-glutamate (Glu), the major excitatory neurotransmitter in the brain, is cleared from the synapse by glutamate transporters (GluTs). The molecular components of Glu synapses are highly conserved between Caenorhabditis elegans and mammals, yet the absence of synaptic insulation in C. elegans raises fundamental questions about Glu clearance strategies in the nematode nervous system. To gain insight into how Glu clearance is accomplished and how GluTs impact neurotransmission, we probed expression and function of all 6 GluTs found in the C. elegans genome. Disruption of each GluT impacts multiple Glu-dependent behaviors, with GluT combinations commonly increasing the severity of behavioral deficits. Interestingly, the sole GluT that we find expressed in neurons is localized predominantly in presynaptic neurons, in contrast to the postsynaptic concentration of neuronal GluTs typical in mammals. Moreover, 3 of the 6 GluT genes appear strongly expressed on the capillary excretory canal cell, where they affect Glu-dependent behaviors from positions distal to glutamatergic circuits. Indeed, our focused study of GLT-3, one of the distally expressed GluTs, shows that despite this distance, GLT-3 function can balance the activity mediated by synaptic release and synaptic receptors. The effects of distal GluTs on glutamatergic circuits support that Glu diffusion outside the vicinity of the synapse is a critical factor in C. elegans neurotransmission. Together with the presynaptic localization of neuronal GluTs, these observations suggest an unusual strategy for Glu clearance in C. elegans.

Received for publication, May 18, 2007 , and in revised form, July 9, 2007.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental information on methods and supplemental Figs. S1-S3.

² Supported by National Institutes of Health Grant HL46154.

¹ Supported by the Human Frontiers Science Foundation (LT0523/1997-B), the ALS Association, and NINDS Grants NS34435 and NS41632 from the National Institutes of Health. To whom correspondence may be addressed: 604 Allison Rd., Piscataway, NJ 08854. Tel.: 732-445-7188; Fax: 732-445-4213; E-mail: mano{at}biology.rutgers.edu.

³ Supported by the ALS Association and NINDS Grants NS34435 and NS41632 from the National Institutes of Health. To whom correspondence may be addressed: 604 Allison Rd., Piscataway, NJ 08854. Tel.: 732-445-7182; Fax: 732-445-7192; E-mail: driscoll{at}biology.rutgers.edu.

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