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Vol. 16, Issue 1, 306-315, January 2005

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Normal Biogenesis and Cycling of Empty Synaptic Vesicles in Dopamine Neurons of Vesicular Monoamine Transporter 2 Knockout Mice

Benjamin G. Croft ^*, Gabriel D. Fortin , Amadou T. Corera ^*, Robert H. Edwards , Alain Beaudet ^*, Louis-Eric Trudeau , and Edward A. Fon ^* 

^* Centre for Neuronal Survival and Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada; Department of Pharmacology, Faculty of Medicine and Groupe de Recherche sur le Système Nerveux Central, Université de Montréal, Montreal, Quebec H3C 3J7, Canada; and Departments of Neurology and Physiology, University of California San Francisco School of Medicine, San Francisco, CA 94143-2140

Submitted July 6, 2004; Accepted October 8, 2004
Monitoring Editor: Lawrence Goldstein

The neuronal isoform of vesicular monoamine transporter, VMAT2, is responsible for packaging dopamine and other monoamines into synaptic vesicles and thereby plays an essential role in dopamine neurotransmission. Dopamine neurons in mice lacking VMAT2 are unable to store or release dopamine from their synaptic vesicles. To determine how VMAT2-mediated filling influences synaptic vesicle morphology and function, we examined dopamine terminals from VMAT2 knockout mice. In contrast to the abnormalities reported in glutamatergic terminals of mice lacking VGLUT1, the corresponding vesicular transporter for glutamate, we found that the ultrastructure of dopamine terminals and synaptic vesicles in VMAT2 knockout mice were indistinguishable from wild type. Using the activity-dependent dyes FM1-43 and FM2-10, we also found that synaptic vesicles in dopamine neurons lacking VMAT2 undergo endocytosis and exocytosis with kinetics identical to those seen in wild-type neurons. Together, these results demonstrate that dopamine synaptic vesicle biogenesis and cycling are independent of vesicle filling with transmitter. By demonstrating that such empty synaptic vesicles can cycle at the nerve terminal, our study suggests that physiological changes in VMAT2 levels or trafficking at the synapse may regulate dopamine release by altering the ratio of fillable-to-empty synaptic vesicles, as both continue to cycle in response to neural activity.

Abbreviations used: VMAT, vesicular monoamine transporter; DA, dopamine; SV, synaptic vesicle; KO, knockout; wt, wild-type; TEM, transmission electron microscopy; PB, phosphate buffer; TH, tyrosine hydroxylase; GLU, glutamate; VGLUT, vesicular glutamate transporter; LDCV, large dense core vesicle; NMJ, neuromuscular junction; ACh, acetylcholine; VAChT, vesicular acetylcholine transporter.

Corresponding author. E-mail address: ted.fon{at}mcgill.ca.

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