The neurotransmitter acetylcholine (ACh) is involved in critical organismal functions that include locomotion and cognition. Importantly, alterations in the cholinergic system are a key underlying factor in cognitive defects associated with aging. One essential component of cholinergic synaptic transmission is the vesicular ACh transporter (VAChT), which regulates the packaging of ACh into synaptic vesicles for extracellular release. Mutations that cause a reduction in either protein level or activity lead to diminished locomotion ability whereas complete loss of function of VAChT is lethal. While much is known about the function of VAChT, the direct role of altered ACh release and its association with either an impairment or an enhancement of cognitive function are still not fully understood. We hypothesize that point mutations in Vacht cause age-related deficits in cholinergic-mediated behaviors such as locomotion, and learning and memory. Using Drosophila melanogaster as a model system, we have studied several mutations within Vacht and observed their effect on survivability and locomotive behavior. Here we report for the first time a weak hypomorphic Vacht allele that shows a differential effect on ACh-linked behaviors. We also demonstrate that partially rescued Vacht point mutations cause an allele-dependent deficit in lifespan and defects in locomotion ability. Moreover, using a thorough data analytics strategy to identify exploratory behavioral patterns, we introduce new paradigms for measuring locomotion-related activities that could not be revealed or detected by a simple measure of the average speed alone. Together, our data indicate a role for VAChT in the maintenance of longevity and locomotion abilities in Drosophila and we provide additional measurements of locomotion that can be useful in determining subtle changes in Vacht function on locomotion-related behaviors.
Keywords: Acetylcholine; Cholinergic release; Vesicular acetylcholine transporter.
Copyright © 2020 Elsevier Ltd. All rights reserved.
Overexpression of the vesicular acetylcholine transporter disrupts cognitive performance and causes age-dependent locomotion decline in Drosophila.Mol Cell Neurosci. 2020 Mar 23;105:103483. doi: 10.1016/j.mcn.2020.103483. Online ahead of print. Mol Cell Neurosci. 2020. PMID: 32217162
Immunolocalization of the vesicular acetylcholine transporter in larval and adult Drosophila neurons.Neurosci Lett. 2017 Mar 16;643:76-83. doi: 10.1016/j.neulet.2017.02.012. Epub 2017 Feb 7. Neurosci Lett. 2017. PMID: 28188850 Free PMC article.
Overexpression of the vesicular acetylcholine transporter increased acetylcholine release in the hippocampus.Neuroscience. 2012 Aug 30;218:1-11. doi: 10.1016/j.neuroscience.2012.05.047. Epub 2012 May 26. Neuroscience. 2012. PMID: 22641085
Microscopic kinetics and structure-function analysis in the vesicular acetylcholine transporter.Neurochem Int. 2002 Nov;41(5):285-9. doi: 10.1016/s0197-0186(02)00058-x. Neurochem Int. 2002. PMID: 12176068 Review.
Regulation of cholinergic activity by the vesicular acetylcholine transporter.Biochem J. 2013 Mar 1;450(2):265-74. doi: 10.1042/BJ20121662. Biochem J. 2013. PMID: 23410039 Review.