Characterization of cognitive impairments and neurotransmitter changes in a novel transgenic mouse lacking Slc10a4

Melief, Erica J.; Gibbs, Jeffrey T.; Li, X.; Morgan, R. Garrett; Keene, C. Dirk; Montine, Thomas J.; Palmiter, Richard D.; Darvas, Martin

doi:10.1016/j.neuroscience.2016.03.037

Cited by 7 publications

(6 citation statements)

References 25 publications

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“…Cognitive flexibility is commonly disrupted in TSC 17 and in several neuropsychiatric conditions including ASD and ADHD 18,46,47 . Dorsal striatal DA signaling has been implicated in cognitive flexibility 48,49 , and decreased striatal DA is associated with reduced cognitive performance 50–52 . We therefore hypothesized that loss of Tsc1 from DA neurons may disrupt cognitive flexibility.…”

Section: Resultsmentioning

confidence: 99%

Tsc1-mTORC1 signaling controls striatal dopamine release and cognitive flexibility

et al. 2019

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Tuberous Sclerosis Complex (TSC) is a neurodevelopmental disorder caused by mutations in TSC1 or TSC2, which encode proteins that negatively regulate mTOR complex 1 (mTORC1). TSC is associated with significant cognitive, psychiatric, and behavioral problems, collectively termed TSC-Associated Neuropsychiatric Disorders (TAND), and the cell types responsible for these manifestations are largely unknown. Here we use cell type-specific Tsc1 deletion to test whether dopamine neurons, which modulate cognitive, motivational, and affective behaviors, are involved in TAND. We show that loss of Tsc1 and constitutive activation of mTORC1 in dopamine neurons causes somatodendritic hypertrophy, reduces intrinsic excitability, alters axon terminal structure, and impairs striatal dopamine release. These perturbations lead to a selective deficit in cognitive flexibility, preventable by genetic reduction of the mTOR-binding protein Raptor. Our results establish a critical role for Tsc1-mTORC1 signaling in setting the functional properties of dopamine neurons, and indicate that dopaminergic dysfunction may contribute to cognitive inflexibility in TSC.

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Section: Resultsmentioning

confidence: 99%

Tsc1-mTORC1 signaling controls striatal dopamine release and cognitive flexibility

et al. 2019

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“…SLC10A4 is a bile acid transporter, about which relatively little is known, including whether it is able to transport bile acids or neurotransmitters (1,103,109). Slc10a4 knockout mice show altered dopamine homeostasis (87,128). MUC4 is major component of intestinal mucus.…”

Section: Evidence For Neurally Mediatedmentioning

confidence: 99%

Sigmoid colon mucosal gene expression supports alterations of neuronal signaling in irritable bowel syndrome with constipation

Videlock

Mahurkar-Joshi

Hoffman

et al. 2018

American Journal of Physiology-Gastrointestinal and Liver Physi

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Peripheral factors likely play a role in at least a subset of irritable bowel syndrome (IBS) patients. Few studies have investigated mucosal gene expression using an unbiased approach. Here, we performed mucosal gene profiling in a sex-balanced sample to identify relevant signaling pathways and gene networks and compare with publicly available profiling data from additional cohorts. Twenty Rome III+ IBS patients [10 IBS with constipation (IBS-C), 10 IBS with diarrhea (IBS-D), 5 men/women each), and 10 age-/sex-matched healthy controls (HCs)] underwent sigmoidoscopy with biopsy for gene microarray analysis, including differential expression, weighted gene coexpression network analysis (WGCNA), gene set enrichment analysis, and comparison with publicly available data. Expression levels of 67 genes were validated in an expanded cohort, including the above samples and 18 additional participants (6 each of IBS-C, IBS-D, HCs) using NanoString nCounter technology. There were 1,270 differentially expressed genes (FDR < 0.05) in IBS-C vs. HCs but none in IBS or IBS-D vs. HCs. WGNCA analysis identified activation of the cAMP/protein kinase A signaling pathway. Nine of 67 genes were validated by the NanoString nCounter technology (FDR < 0.05) in the expanded sample. Comparison with publicly available microarray data from the Mayo Clinic and University of Nottingham supports the reproducibility of 17 genes from the microarray analysis and three of nine genes validated by nCounter in IBS-C vs. HCs. This study supports the involvement of peripheral mechanisms in IBS-C, particularly pathways mediating neuronal signaling. NEW & NOTEWORTHY Peripheral factors play a role in the pathophysiology of irritable bowel syndrome (IBS), which, to date, has been mostly evident in IBS with diarrhea. Here, we show that sigmoid colon mucosal gene expression profiles differentiate IBS with constipation from healthy controls. These profiling data and analysis of additional cohorts also support the concept that peripheral neuronal pathways contribute to IBS pathophysiology.

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“…While these three transporters have been well characterized, this family contains four additional proteins, namely P3 ( SLC10A3 ), P4 ( SLC10A4 ), P5 ( SLC10A5 ), and P7 ( SLC10A7 ), with mostly unknown function. To try to understand the function of SLC10A4 (a "transporter" expressed in humans in the developing ventral mesencephalon 56 and in rats in cholinergic and monoaminergic neurons 57 ), mice lacking SLC10A4 protein were recently characterized 58 – 60 . No direct transporter function could be demonstrated for SLC10A4, but its absence reduced dopamine, noradrenaline, serotonin, and acetylcholine content in certain brain regions.…”

Section: Deorphanizing Slc Transportersmentioning

confidence: 99%

“…These few examples highlight the pressing need for "deorphanizing" the SLC transporters completely. Possible methods may include the generation of knockout mice as described for SLC10A4 58 , 60 , the use of haploid genetic screens, which was successful in the identification of a function for SLC35F2 62 , and possibly siRNA screens when a transporter for a given function needs to be identified.…”

Section: Deorphanizing Slc Transportersmentioning

confidence: 99%

Recent advances in understanding hepatic drug transport

Stieger

Hagenbuch

2016

F1000Res

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Cells need to strictly control their internal milieu, a function which is performed by the plasma membrane. Selective passage of molecules across the plasma membrane is controlled by transport proteins. As the liver is the central organ for drug metabolism, hepatocytes are equipped with numerous drug transporters expressed at the plasma membrane. Drug disposition includes absorption, distribution, metabolism, and elimination of a drug and hence multiple passages of drugs and their metabolites across membranes. Consequently, understanding the exact mechanisms of drug transporters is essential both in drug development and in drug therapy. While many drug transporters are expressed in hepatocytes, and some of them are well characterized, several transporters have only recently been identified as new drug transporters. Novel powerful tools to deorphanize (drug) transporters are being applied and show promising results. Although a large set of tools are available for studying transport in vitro and in isolated cells, tools for studying transport in living organisms, including humans, are evolving now and rely predominantly on imaging techniques, e.g. positron emission tomography. Imaging is an area which, certainly in the near future, will provide important insights into "transporters at work" in vivo.

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Characterization of cognitive impairments and neurotransmitter changes in a novel transgenic mouse lacking Slc10a4

Cited by 7 publications

References 25 publications

Tsc1-mTORC1 signaling controls striatal dopamine release and cognitive flexibility

Tsc1-mTORC1 signaling controls striatal dopamine release and cognitive flexibility

Sigmoid colon mucosal gene expression supports alterations of neuronal signaling in irritable bowel syndrome with constipation

Recent advances in understanding hepatic drug transport

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