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Expression and immunolocalization of the plasma membrane monoamine transporter in the brain.

ABSTRACT: High affinity monoamine transporters efficiently terminate neurotransmission through synaptic reuptake of released neurotransmitter. We recently cloned and characterized a novel low-affinity, high capacity plasma membrane monoamine transporter (PMAT) that is strongly expressed in the human brain and efficiently transports 5-HT and dopamine (DA). In efforts to understand the physiological function of PMAT and its relevance in monoaminergic pathways, we cloned the PMAT homolog from the mouse brain, demonstrated its capability for transporting 5-HT and DA, and determined the regional and cellular localization of mouse plasma membrane monoamine transporter (mPMAT) in adult mouse brain by reverse-transcription polymerase chain reaction, non-radioactive in situ hybridization, and immunohistochemical methods. Our results showed that mPMAT mRNA and protein are broadly expressed in the mouse brain and are particularly abundant in forebrain cortex, olfactory tubercle, hippocampus, cerebellum and epithelial cells of the choroid plexus. Dual-immunofluorescence histochemistry with established phenotypic markers microtubule-associated protein (MAP2) and glial fibrillary acidic protein (GFAP) revealed that mPMAT is expressed in neuronal cells but not in astrocytes. mPMAT is co-expressed in many brain regions with the high affinity 5-HT transporter (SERT) and the dopamine transporter (DAT), but is also found in certain sites that receive monoamine innervation but lack significant expression of SERT or DAT. These findings suggest that mPMAT is a widely distributed, neuronally-expressed transporter, which may support the role of 5-HT and DA uptake under certain conditions.

SUBMITTER: Dahlin A

PROVIDER: S-EPMC2683847 | biostudies-literature | 2007 May

REPOSITORIES: biostudies-literature

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Expression and immunolocalization of the plasma membrane monoamine transporter in the brain.

Dahlin A A Xia L L Kong W W Hevner R R Wang J J

Neuroscience 20070403 3

High affinity monoamine transporters efficiently terminate neurotransmission through synaptic reuptake of released neurotransmitter. We recently cloned and characterized a novel low-affinity, high capacity plasma membrane monoamine transporter (PMAT) that is strongly expressed in the human brain and efficiently transports 5-HT and dopamine (DA). In efforts to understand the physiological function of PMAT and its relevance in monoaminergic pathways, we cloned the PMAT homolog from the mouse brain ...[more]

PMID: 17408864

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Project description:BackgroundPatients with autism spectrum disorder (ASD) may have low brain serotonin concentrations as reflected by the serotonin end-metabolite 5-hydroxyindolacetic acid (5HIAA) in cerebrospinal fluid (CSF).MethodsWe sequenced the candidate genes SLC6A4 (SERT), SLC29A4 (PMAT), and GCHFR (GFRP), followed by whole exome analysis.ResultsThe known heterozygous p.Gly56Ala mutation in the SLC6A4 gene was equally found in the ASD and control populations. Using a genetic candidate gene approach, we identified, in 8 patients of a cohort of 248 with ASD, a high prevalence (3.2%) of three novel heterozygous non-synonymous mutations within the SLC29A4 plasma membrane monoamine transporter (PMAT) gene, c.86A > G (p.Asp29Gly) in two patients, c.412G > A (p.Ala138Thr) in five patients, and c.978 T > G (p.Asp326Glu) in one patient. Genome analysis of unaffected parents confirmed that these PMAT mutations were not de novo but inherited mutations. Upon analyzing over 15,000 normal control chromosomes, only SLC29A4 c.86A > G was found in 23 alleles (0.14%), while neither c.412G > A (<0.007%) nor c.978 T > G (<0.007%) were observed in all chromosomes analyzed, emphasizing the rareness of the three alterations. Expression of mutations PMAT-p.Ala138Thr and p.Asp326Glu in cellulae revealed significant reduced transport uptake activity towards a variety of substrates including serotonin, dopamine, and 1-methyl-4-phenylpyridinium (MPP(+)), while mutation p.Asp29Gly had reduced transport activity only towards MPP(+). At least two ASD subjects with either the PMAT-Ala138Thr or the PMAT-Asp326Glu mutation with altered serotonin transport activity had, besides low 5HIAA in CSF, elevated serotonin levels in blood and platelets. Moreover, whole exome sequencing revealed additional alterations in these two ASD patients in mainly serotonin-homeostasis genes compared to their non-affected family members.ConclusionsOur findings link mutations in SLC29A4 to the ASD population although not invariably to low brain serotonin. PMAT dysfunction is speculated to raise serotonin prenatally, exerting a negative feedback inhibition through serotonin receptors on development of serotonin networks and local serotonin synthesis. Exome sequencing of serotonin homeostasis genes in two families illustrated more insight in aberrant serotonin signaling in ASD.

Project description:Background: Brain development and maturation in adolescence is a complex process with active changes of metabolic and neurotransmission pathways. Positron emission tomography (PET) is a useful imaging modality for tracking metabolic and functional changes in adolescent brain. In this study, changes of glucose metabolism, expression of vesicular monoamine transporter 2 and dopamine transporter during adolescent brain development in rats were investigated with PET/CT. Methods: A longitudinal PET/CT study of age-dependent changes of VMAT2, DAT and glucose metabolism in adolescent brain was conducted in a group of Wistar rats (n = 6) post sequential intravenous injection of 18F-PF-(+)-DTBZ, 11C-CFT, and 18F-FDG, respectively. PET acquisition was performed at 2, 4, 9, and 12 months of age. Radiotracer uptake in different brain regions, including the striatum, cerebellum, and hippocampus, were quantified and recorded as Standardized uptake value (SUV) and striatal specific uptake ratio (SUVR: SUV in brain regions/SUV in cerebellum). Results: Variable uptake of 18F-PF-(+)-DTBZ and 11C-CFT were detected, with highest level uptake in the striatum and accumbens. There was significant age-dependent increase of 18F-PF-(+)-DTBZ and 11C-CFT uptake in the striatum from 2 months of age (SUV: 1.36 ± 0.22, 1.37 ± 0.39, respectively), to 4 months (SUV: 2.22 ± 0.29, 2.04 ± 0.33), 9 months (1.98 ± 0.34, 2.09 ± 0.18), 12 months (SUV: 1.93 ± 0.19, 2.00 ± 0.17) of age, SUV of 18F-FDG also increased from 2 months of age to older ages (SUV in the striatum: 3.71 ± 0.78 at 2 month, 5.28 ± 0.81, 5.14 ± 0.73, 4.94 ± 0.50 at 4, 9, 12 month, respectively). Conclusion: Age-dependent increases of striatal of 18F-FDG, 18F-PF-(+)-DTBZ, and 11C-CFT uptake were detected in rats from 2 to 4 month of age, demonstrating striatal development presents over the first 4 months of age. Four months of age can be considered a safe threshold to launch brain disease studies for exclusion of confusion of continuing tissue development. These findings support further investigation of age-dependent changes in expression of DAT, VMAT2, and glucose metabolism for their potential use as a new imaging biomarker for study of brain development and functional maturation.

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Expression and immunolocalization of the plasma membrane monoamine transporter in the brain.

Publications

Expression and immunolocalization of the plasma membrane monoamine transporter in the brain.

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