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The Journal of Neuroscience, December 19, 2007, 27(51):14216-14227; doi:10.1523/JNEUROSCI.2992-07.2007

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Cellular/Molecular
Vigorous Motor Activity in Caenorhabditis elegans Requires Efficient Clearance of Dopamine Mediated by Synaptic Localization of the Dopamine Transporter DAT-1

Paul W. McDonald,^1 * Shannon L. Hardie,^1 * Tammy N. Jessen,¹ Lucia Carvelli,¹ Dawn Signor Matthies,¹ and Randy D. Blakely^1,2,3

Departments of ¹Pharmacology and ²Psychiatry and ³Center for Molecular Neuroscience, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-8548

Correspondence should be addressed to Dr. Randy D. Blakely, Suite 7140, MRB III, Center for Molecular Neuroscience, Nashville, TN 27232-8548. Email: randy.blakely{at}vanderbilt

The catecholamine dopamine (DA) functions as a powerful modulatory neurotransmitter in both invertebrates and vertebrates. As in man, DA neurons in the nematode Caenorhabditis elegans express a cocaine-sensitive transporter (DAT-1), presumably to regulate synaptic DA signaling and limit DA spillover to extrasynaptic sites, although evidence supporting this is currently lacking. In this report, we describe and validate a novel and readily quantifiable phenotype, swimming-induced paralysis (SWIP) that emerges in DAT-1-deficient nematodes when animals exert maximal physical activity in water. We verify the dependence of SWIP on DA biosynthesis, vesicular packaging, synaptic release, and on the DA receptor DOP-3. Using DAT-1 specific antibodies and GFP::DAT-1 fusions, we demonstrate a synaptic enrichment of DAT-1 that is achieved independently of synaptic targeting of the vesicular monoamine transporter (VMAT). Importantly, dat-1 deletions and point mutations that disrupt DA uptake in cultured C. elegans neurons and/or impact DAT-1 synaptic localization in vivo generate SWIP. SWIP assays, along with in vivo imaging of wild-type and mutant GFP::DAT-1 fusions identify a distal COOH terminal segment of the transporter as essential for efficient somatic export, synaptic localization and in vivo DA clearance. Our studies provide the first description of behavioral perturbations arising from altered trafficking of DATs in vivo in any organism and support a model whereby endogenous DA actions in C. elegans are tightly regulated by synaptic DAT-1.

Key words: dopamine; transporter; receptor; C. elegans; dat-1; synapse; localization; PDZ binding domain; unc-104; cat-1

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Received July 1, 2007; revised Oct. 16, 2007; accepted Nov. 13, 2007.

Correspondence should be addressed to Dr. Randy D. Blakely, Suite 7140, MRB III, Center for Molecular Neuroscience, Nashville, TN 27232-8548. Email: randy.blakely{at}vanderbilt

This article has been cited by other articles:

				M. M. Gaglia and C. Kenyon Stimulation of Movement in a Quiescent, Hibernation-Like Form of Caenorhabditis elegans by Dopamine Signaling J. Neurosci., June 3, 2009; 29(22): 7302 - 7314. [Abstract] [Full Text] [PDF]

				L. Carvelli, R. D. Blakely, and L. J. DeFelice Dopamine transporter/syntaxin 1A interactions regulate transporter channel activity and dopaminergic synaptic transmission PNAS, September 16, 2008; 105(37): 14192 - 14197. [Abstract] [Full Text] [PDF]

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