The redistribution of Drosophila vesicular monoamine transporter mutants from synaptic vesicles to large dense-core vesicles impairs amine-dependent behaviors.
Monoamine neurotransmitters are stored in both synaptic vesicles (SVs), which are required for release at the synapse, and large dense-core vesicles (LDCVs), which mediate extrasynaptic release. The contributions of each type of vesicular release to specific behaviors are not known. To address this issue, we generated mutations in the C-terminal trafficking domain of the Drosophila vesicular monoamine transporter (DVMAT), which is required for the vesicular storage of monoamines in both SVs and LDCVs. Deletion of the terminal 23 aa (DVMAT-Δ3) reduced the rate of endocytosis and localization of DVMAT to SVs, but supported localization to LDCVs. An alanine substitution mutation in a tyrosine-based motif (DVMAT-Y600A) also reduced sorting to SVs and showed an endocytic deficit specific to aminergic nerve terminals. Redistribution of DVMAT-Y600A from SV to LDCV fractions was also enhanced in aminergic neurons. To determine how these changes might affect behavior, we expressed DVMAT-Δ3 and DVMAT-Y600A in a dVMAT null genetic background that lacks endogenous dVMAT activity. When expressed ubiquitously, DVMAT-Δ3 showed a specific deficit in female fertility, whereas DVMAT-Y600A rescued behavior similarly to DVMAT-wt. In contrast, when expressed more specifically in octopaminergic neurons, both DVMAT-Δ3 and DVMAT-Y600A failed to rescue female fertility, and DVMAT-Y600A showed deficits in larval locomotion. DVMAT-Y600A also showed more severe dominant effects than either DVMAT-wt or DVMAT-Δ3. We propose that these behavioral deficits result from the redistribution of DVMAT from SVs to LDCVs. By extension, our data suggest that the balance of amine release from SVs versus that from LDCVs is critical for the function of some aminergic circuits.
Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, Hatos Center for Neuropharmacology, David Geffen School of Medicine.
Anna
A
Grygoruk
Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, Hatos Center for Neuropharmacology, David Geffen School of Medicine, Department of Neurobiology, and.
Audrey
A
Chen
Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, Hatos Center for Neuropharmacology, David Geffen School of Medicine, Interdepartmental Program in Molecular Toxicology, University of California, Los Angeles, Los Angeles, California 90095, and.
Ciara A
CA
Martin
Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, Hatos Center for Neuropharmacology, David Geffen School of Medicine.
Hakeem O
HO
Lawal
Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, Hatos Center for Neuropharmacology, David Geffen School of Medicine.
Hao
H
Fei
Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, Hatos Center for Neuropharmacology, David Geffen School of Medicine.
Gabriel
G
Gutierrez
Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, Hatos Center for Neuropharmacology, David Geffen School of Medicine.
Traci
T
Biedermann
Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, Hatos Center for Neuropharmacology, David Geffen School of Medicine.
Rod
R
Najibi
Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, Hatos Center for Neuropharmacology, David Geffen School of Medicine.
Richard
R
Hadi
Department of Physiology, University of Texas Health Science Center, San Antonio, San Antonio, Texas 78229.
Amit K
AK
Chouhan
Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, Hatos Center for Neuropharmacology, David Geffen School of Medicine.
Niall P
NP
Murphy
Department of Neurobiology, and.
Felix E
FE
Schweizer
Department of Physiology, University of Texas Health Science Center, San Antonio, San Antonio, Texas 78229.
Gregory T
GT
Macleod
Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, Hatos Center for Neuropharmacology, David Geffen School of Medicine.
Nigel T
NT
Maidment
Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, Hatos Center for Neuropharmacology, David Geffen School of Medicine, dkrantz@ucla.edu.
David E
DE
Krantz
D000818:Animals; D030801:Animals, Genetically Modified; D001522:Behavior, Animal / Q000502:physiology*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster; D005260:Female; D022142:Secretory Vesicles / Q000378:metabolism*; D013572:Synaptic Vesicles / Q000378:metabolism*; D050493:Vesicular Monoamine Transport Proteins / Q000235:genetics / Q000378:metabolism*
D029721:Drosophila Proteins; D050493:Vesicular Monoamine Transport Proteins
LDCV; dopamine; octopamine; serotonin; synaptic; vmat