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Vesicular monoamine transporter trafficking affects mode of neurotransmitter release and microcircuit function

囊泡单胺转运蛋白运输影响神经递质释放模式和微电路功能

基本信息

批准号：
9765409
负责人：
James Edward Laurel Dizon Asuncion
金额：
$ 4.5万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-19 至 2020-09-18
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9765409
关键词：
Affect Aggressive behavior Alleles Amines Animals Antidepressive Agents Attention Behavior Behavioral C-terminal CRISPR/Cas technology Calcium Cell membrane Cells Complex DNA Data Dense Core Vesicle Dopamine Drosophila genus Drosophila melanogaster Equilibrium Functional disorder Genes Genetic Genetic Models Genetic Screening Glutamates Image Imaging Techniques Invertebrates Laboratories Link Logic Mediating Membrane Transport Proteins Mental Depression Mental disorders Modeling Molecular Molecular Genetics Mood Disorders Moods Muscle Muscle Contraction Mutation Nerve Nervous system structure Neuroanatomy Neurons Neurotransmitters Octopamine Organ Other Genetics Oviposition Pathway interactions Pattern Periodicity Pharmaceutical Preparations Pharmacology Phenocopy Process Psychiatry Secretory Vesicles Serotonin Signal Transduction Site Sleep Synapses Synaptic Transmission Synaptic Vesicles System Testing Therapeutic Transgenes Transgenic Organisms experimental study extracellular functional restoration insertion/deletion mutation monoamine mutant neuroregulation neurotransmission neurotransmitter release neurotransmitter reuptake noradrenaline transporter novel novel therapeutics null mutation optogenetics protein transport receptor repaired research and development synaptic function therapeutic target tool trafficking vesicular monoamine transporter vesicular release

项目摘要

Abstract Monoamine neurotransmitters, such as dopamine and serotonin, modulate fast synaptic transmission in circuits that mediate many complex behaviors including aggression, sleep, attention, and mood. In psychiatry, many therapeutics target monoamine systems at either the receptors or transporters that mediate and regulate monoamine neurotransmission. The vesicular monoamine transporter (VMAT) is responsible for loading all monoamine neurotransmitters into both synaptic vesicles (SVs) and large dense-core vesicles (LDCVs), which mediate synaptic and extrasynaptic release, respectively. However, the functional contribution of each type of vesicular release to circuit function and behavior is unknown. Previous studies in Drosophila have demonstrated that the amount and site of amine release can be altered by mutations in the C-terminal trafficking domain of Drosophila VMAT (DVMAT). In a DVMAT null genetic background, the function of several circuits and behaviors are perturbed, but are rescued by transgenic expression of wild-type and trafficking mutant alleles. However, some behaviors are not rescued by trafficking mutants. Mutations that cause DVMAT to preferentially traffic to LDCVs do not rescue function of the oviposition circuit. This suggests that the oviposition circuit is highly sensitive to the delicate balance between synaptic and extrasynaptic release of the neurotransmitter octopamine (OA). I hypothesize that trafficking mutations in the endogenous DVMAT gene locus will confer circuit dysfunction, resembling genetic rescue experiments. To further test this idea, I propose to create a new genetic model of DVMAT trafficking using CRISPR/Cas9 to alter trafficking signals in the endogenous gene. My preliminary data demonstrate that indel mutations that disrupt the DVMAT C-terminus phenocopy previous experiments. This novel genetic model will be useful to study the effects of mutants at endogenous expression levels, facilitates combinations with genetic and molecular tools for circuit analysis, and represents a new platform for genetic screens to find novel regulators of DVMAT function. I propose to study the contributions of the different modes of monoamine release in the Drosophila melanogaster oviposition microcircuit. I hypothesize that alteration of the mode of amine release will result in patterns of muscular contractions and rhythmic activity in target organs that will differ from wild-type animals. These proposed studies will elucidate novel mechanisms of aminergic signaling and new avenues for the research and development of new therapeutics for psychiatric disorders.

摘要