The polyamine transporter Slc18b1(VPAT) is important for both short and long time memory and for regulation of polyamine content in the brain
Open Access
- 4 December 2019
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLoS Genetics
- Vol. 15 (12), e1008455
- https://doi.org/10.1371/journal.pgen.1008455
Abstract
SLC18B1 is a sister gene to the vesicular monoamine and acetylcholine transporters, and the only known polyamine transporter, with unknown physiological role. We reveal that Slc18b1 knock out mice has significantly reduced polyamine content in the brain providing the first evidence that Slc18b1 is functionally required for regulating polyamine levels. We found that this mouse has impaired short and long term memory in novel object recognition, radial arm maze and self-administration paradigms. We also show that Slc18b1 KO mice have altered expression of genes involved in Long Term Potentiation, plasticity, calcium signalling and synaptic functions and that expression of components of GABA and glutamate signalling are changed. We further observe a partial resistance to diazepam, manifested as significantly lowered reduction in locomotion after diazepam treatment. We suggest that removal of Slc18b1 leads to reduction of polyamine contents in neurons, resulting in reduced GABA signalling due to long-term reduction in glutamatergic signalling. A fundamental function of the nervous system is its ability to modulate and change the connections between nerve cells, and this forms the basis for memory and learning. This is most well studied for synapses that are using the neurotransmitter glutamate, and a central part of this is referred to Long Term Potentiation. This process is dependent on a specific glutamate receptor called the NMDA receptor, and the function of this receptor can be controlled by various mechanisms. Here, we show that polyamines can regulate this receptor and that lack of polyamines result in impaired learning and memory. Polyamines are small peptides made by many different cells in the body, including cells in the brain, and by removing a gene coding for a transporter important for the release of polyamines in nerve cells of mice, we show that polyamines are important for proper function of the glutamate system. We also show the deletion of this gene result in fundamentally rearranged GABA and glutamate systems, resulting in the mice having a much higher tolerance for the sedative drug benzodiazepines. Polyamines and targets for these molecules could be important points of intervention for future drugs aiming at modulating the glutamatergic system.Keywords
This publication has 70 references indexed in Scilit:
- Characterization of the transporterB0AT3 (Slc6a17) in the rodent central nervous systemBMC Neuroscience, 2013
- Rab14 and Its Exchange Factor FAM116 Link Endocytic Recycling and Adherens Junction Stability in Migrating CellsDevelopmental Cell, 2012
- The novel object recognition memory: neurobiology, test procedure, and its modificationsCognitive Processing, 2011
- Mammalian polyamine metabolism and functionIUBMB Life, 2009
- Tubulin modifications and their cellular functionsCurrent Opinion in Cell Biology, 2008
- PLINK: A Tool Set for Whole-Genome Association and Population-Based Linkage AnalysesAmerican Journal of Human Genetics, 2007
- The use of the elevated plus maze as an assay of anxiety-related behavior in rodentsNature Protocols, 2007
- HMDB: the Human Metabolome DatabaseNucleic Acids Research, 2007
- Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profilesProceedings of the National Academy of Sciences of the United States of America, 2005
- PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetesNature Genetics, 2003