Publications by authors named "Georg Dechant"

42 Publications

Involvement of cAMP-Dependent Protein Kinase in the Nucleus Accumbens in Cocaine Versus Social Interaction Reward.

Int J Mol Sci 2020 Dec 31;22(1). Epub 2020 Dec 31.

Division of Psychiatry I, Department of Psychiatry, Psychotherapy and Psychosomatics, Medical University Innsbruck, 6020 Innsbruck, Austria.

Evidence suggests that PKA activity in the nucleus accumbens (NAc) plays an essential role in reward-related learning. In this study, we investigated whether PKA is differentially involved in the expression of learning produced by either natural reinforcers or psychostimulants. For that purpose, we inhibited PKA through a bilateral infusion of Rp-cAMPS, a specific PKA inhibitor, directly into the NAc. The effects of PKA inhibition in the NAc on the expression of concurrent conditioned place preference (CPP) for cocaine (drug) and social interaction (natural reward) in rats were evaluated. We found that PKA inhibition increased the expression of cocaine preference. This effect was not due to altered stress levels or decreased social reward. PKA inhibition did not affect the expression of natural reward as intra-NAc Rp-cAMPS infusion did not affect expression of social preference. When rats were trained to express cocaine or social interaction CPP and tested for eventual persisting preference 7 and 14 days after CPP expression, cocaine preference was persistent, but social preference was abolished after the first test. These results suggest that PKA in the NAc is involved in drug reward learning that might lead to addiction and that only drug, but not natural, reward is persistent.
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http://dx.doi.org/10.3390/ijms22010345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794935PMC
December 2020

SATB2-LEMD2 interaction links nuclear shape plasticity to regulation of cognition-related genes.

EMBO J 2021 Feb 15;40(3):e103701. Epub 2020 Dec 15.

Institute for Neuroscience, Medical University of Innsbruck, Innsbruck, Austria.

SATB2 is a schizophrenia risk gene and is genetically associated with human intelligence. How it affects cognition at molecular level is currently unknown. Here, we show that interactions between SATB2, a chromosomal scaffolding protein, and the inner nuclear membrane protein LEMD2 orchestrate the response of pyramidal neurons to neuronal activation. Exposure to novel environment in vivo causes changes in nuclear shape of CA1 hippocampal neurons via a SATB2-dependent mechanism. The activity-driven plasticity of the nuclear envelope requires not only SATB2, but also its protein interactor LEMD2 and the ESCRT-III/VPS4 membrane-remodeling complex. Furthermore, LEMD2 depletion in cortical neurons, similar to SATB2 ablation, affects neuronal activity-dependent regulation of multiple rapid and delayed primary response genes. In human genetic data, LEMD2-regulated genes are enriched for de novo mutations reported in intellectual disability and schizophrenia and are, like SATB2-regulated genes, enriched for common variants associated with schizophrenia and cognitive function. Hence, interactions between SATB2 and the inner nuclear membrane protein LEMD2 influence gene expression programs in pyramidal neurons that are linked to cognitive ability and psychiatric disorder etiology.
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http://dx.doi.org/10.15252/embj.2019103701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849313PMC
February 2021

Social interaction reward in rats has anti-stress effects.

Addict Biol 2021 01 26;26(1):e12878. Epub 2020 Jan 26.

Department of Psychiatry, Psychotherapy and Psychosomatics, Division of Psychiatry I, Medical University Innsbruck, Innsbruck, Austria.

Social interaction in an alternative context can be beneficial against drugs of abuse. Stress is known to be a risk factor that can exacerbate the effects of addictive drugs. In this study, we investigated whether the positive effects of social interaction are mediated through a decrease in stress levels. For that purpose, rats were trained to express cocaine or social interaction conditioned place preference (CPP). Behavioural, hormonal, and molecular stress markers were evaluated. We found that social CPP decreased the percentage of incorrect transitions of grooming and corticosterone to the level of naïve untreated rats. In addition, corticotropin-releasing factor (CRF) was increased in the bed nucleus of stria terminalis after cocaine CPP. In order to study the modulation of social CPP by the CRF system, rats received intracerebroventricular CRF or alpha-helical CRF, a nonselective antagonist of CRF receptors. The subsequent effects on CPP to cocaine or social interaction were observed. CRF injections increased cocaine CPP, whereas alpha-helical CRF injections decreased cocaine CPP. However, alpha-helical CRF injections potentiated social CPP. When social interaction was made available in an alternative context, CRF-induced increase of cocaine preference was reversed completely to the level of rats receiving cocaine paired with alpha-helical CRF. This reversal of cocaine preference was also paralleled by a reversal in CRF-induced increase of p38 MAPK expression in the nucleus accumbens shell. These findings suggest that social interaction could contribute as a valuable component in treatment of substance use disorders by reducing stress levels.
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http://dx.doi.org/10.1111/adb.12878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757251PMC
January 2021

Genes encoding SATB2-interacting proteins in adult cerebral cortex contribute to human cognitive ability.

PLoS Genet 2019 02 6;15(2):e1007890. Epub 2019 Feb 6.

Institute for Neuroscience, Medical University of Innsbruck, Innsbruck, Austria.

During CNS development, the nuclear protein SATB2 is expressed in superficial cortical layers and determines projection neuron identity. In the adult CNS, SATB2 is expressed in pyramidal neurons of all cortical layers and is a regulator of synaptic plasticity and long-term memory. Common variation in SATB2 locus confers risk of schizophrenia, whereas rare, de novo structural and single nucleotide variants cause severe intellectual disability and absent or limited speech. To characterize differences in SATB2 molecular function in developing vs adult neocortex, we isolated SATB2 protein interactomes at the two ontogenetic stages and identified multiple novel SATB2 interactors. SATB2 interactomes are highly enriched for proteins that stabilize de novo chromatin loops. The comparison between the neonatal and adult SATB2 protein complexes indicates a developmental shift in SATB2 molecular function, from transcriptional repression towards organization of chromosomal superstructure. Accordingly, gene sets regulated by SATB2 in the neocortex of neonatal and adult mice show limited overlap. Genes encoding SATB2 protein interactors were grouped for gene set analysis of human GWAS data. Common variants associated with human cognitive ability are enriched within the genes encoding adult but not neonatal SATB2 interactors. Our data support a shift in the function of SATB2 in cortex over lifetime and indicate that regulation of spatial chromatin architecture by the SATB2 interactome contributes to cognitive function in the general population.
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http://dx.doi.org/10.1371/journal.pgen.1007890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6364870PMC
February 2019

Cocaine Paired Environment Increases SATB2 Levels in the Rat Paraventricular Thalamus.

Front Behav Neurosci 2018 2;12:224. Epub 2018 Oct 2.

Experimental Psychiatry Unit, Medical University of Innsbruck, Innsbruck, Austria.

SATB2 is a DNA binding protein that specifically binds the nuclear matrix attachment region and functions as a regulator of the transcription of large chromatin domains. Unlike its well addressed role during brain development, the role of SATB2 in adult brain is under-investigated. It has been shown that deletion of SATB2 from the forebrain of adult mice significantly impaired long-term memory for contextual fear and object recognition memory. The aim of the present study was to investigate the effects of appetitive stimuli such as cocaine and social interaction (SI) on SATB2 expression in the adult rat brain. For that, we performed conditioned place preference (CPP) to cocaine (15 mg/kg) and to SI, then assessed SATB2 expression in the brain 1 h (24 h after the last conditioning) and 24 h (48 h after the last conditioning) after the CPP test. We found that SATB2 expression in the paraventricular thalamus of rats was increased 1 h after the cocaine CPP test. This increase was selective for the cocaine-paired environment since the SI-paired environment did not increase SATB2 expression in the paraventricular thalamus. Also, the cocaine paired environment-induced increase of SATB2 levels in the paraventricular thalamus was due to cocaine conditioning as the unpaired cocaine group did not show an increase of SATB2 in the paraventricular thalamus. These results suggest that SATB2 in the paraventricular thalamus appears to be involved in the association between cocaine effects and environmental context. Further studies are needed to address the functional role of SATB2 in cocaine conditioning.
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http://dx.doi.org/10.3389/fnbeh.2018.00224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6190852PMC
October 2018

Genes regulated by SATB2 during neurodevelopment contribute to schizophrenia and educational attainment.

PLoS Genet 2018 07 24;14(7):e1007515. Epub 2018 Jul 24.

Cognitive Genetics and Cognitive Therapy Group, Neuroimaging, Cognition and Genomics (NICOG) Centre and NCBES Galway Neuroscience Centre, School of Psychology and Discipline of Biochemistry, National University of Ireland Galway, Galway, Ireland.

SATB2 is associated with schizophrenia and is an important transcription factor regulating neocortical organization and circuitry. Rare mutations in SATB2 cause a syndrome that includes developmental delay, and mouse studies identify an important role for SATB2 in learning and memory. Interacting partners BCL11B and GATAD2A are also schizophrenia risk genes indicating that other genes interacting with or are regulated by SATB2 are making a contribution to schizophrenia and cognition. We used data from Satb2 mouse models to generate three gene-sets that contain genes either functionally related to SATB2 or targeted by SATB2 at different stages of development. Each was tested for enrichment using the largest available genome-wide association studies (GWAS) datasets for schizophrenia and educational attainment (EA) and enrichment analysis was also performed for schizophrenia and other neurodevelopmental disorders using data from rare variant sequencing studies. These SATB2 gene-sets were enriched for genes containing common variants associated with schizophrenia and EA, and were enriched for genes containing rare variants reported in studies of schizophrenia, autism and intellectual disability. In the developing cortex, genes targeted by SATB2 based on ChIP-seq data, and functionally affected when SATB2 is not expressed based on differential expression analysis using RNA-seq data, show strong enrichment for genes associated with EA. For genes expressed in the hippocampus or at the synapse, those targeted by SATB2 are more strongly enriched for genes associated EA than gene-sets not targeted by SATB2. This study demonstrates that single gene findings from GWAS can provide important insights to pathobiological processes. In this case we find evidence that genes influenced by SATB2 and involved in synaptic transmission, axon guidance and formation of the corpus callosum are contributing to schizophrenia and cognition.
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http://dx.doi.org/10.1371/journal.pgen.1007515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097700PMC
July 2018

Bicistronic CACNA1A Gene Expression in Neurons Derived from Spinocerebellar Ataxia Type 6 Patient-Induced Pluripotent Stem Cells.

Stem Cells Dev 2017 11 30;26(22):1612-1625. Epub 2017 Oct 30.

1 Institute for Neuroscience, Medical University of Innsbruck , Innsbruck, Austria .

Spinocerebellar ataxia type 6 (SCA6) is an autosomal-dominant neurodegenerative disorder that is caused by a CAG trinucleotide repeat expansion in the CACNA1A gene. As one of the few bicistronic genes discovered in the human genome, CACNA1A encodes not only the α1A subunit of the P/Q type voltage-gated Ca channel Ca2.1 but also the α1ACT protein, a 75 kDa transcription factor sharing the sequence of the cytoplasmic C-terminal tail of the α1A subunit. Isoforms of both proteins contain the polyglutamine (polyQ) domain that is expanded in SCA6 patients. Although certain SCA6 phenotypes appear to be specific for Purkinje neurons, other pathogenic effects of the SCA6 polyQ mutation can affect a broad spectrum of central nervous system (CNS) neuronal subtypes. We investigated the expression and function of CACNA1A gene products in human neurons derived from induced pluripotent stem cells from two SCA6 patients. Expression levels of CACNA1A encoding α1A subunit were similar between SCA6 and control neurons, and no differences were found in the subcellular distribution of Ca2.1 channel protein. The α1ACT immunoreactivity was detected in the majority of cell nuclei of SCA6 and control neurons. Although no SCA6 genotype-dependent differences in Ca2.1 channel function were observed, they were found in the expression levels of the α1ACT target gene Granulin (GRN) and in glutamate-induced cell vulnerability.
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http://dx.doi.org/10.1089/scd.2017.0085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5684673PMC
November 2017

Satb2 determines miRNA expression and long-term memory in the adult central nervous system.

Elife 2016 11 29;5. Epub 2016 Nov 29.

Institute for Neuroscience, Medical University of Innsbruck, Innsbruck, Austria.

is a risk locus for schizophrenia and encodes a DNA-binding protein that regulates higher-order chromatin configuration. In the adult brain Satb2 is almost exclusively expressed in pyramidal neurons of two brain regions important for memory formation, the cerebral cortex and the CA1-hippocampal field. Here we show that Satb2 is required for key hippocampal functions since deletion of Satb2 from the adult mouse forebrain prevents the stabilization of synaptic long-term potentiation and markedly impairs long-term fear and object discrimination memory. At the molecular level, we find that synaptic activity and BDNF up-regulate Satb2, which itself binds to the promoters of coding and non-coding genes. Satb2 controls the hippocampal levels of a large cohort of miRNAs, many of which are implicated in synaptic plasticity and memory formation. Together, our findings demonstrate that Satb2 is critically involved in long-term plasticity processes in the adult forebrain that underlie the consolidation and stabilization of context-linked memory.
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http://dx.doi.org/10.7554/eLife.17361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5207769PMC
November 2016

Reduced Anxiety-Like Behavior and Altered Hippocampal Morphology in Female p75NTR(exon IV-/-) Mice.

Front Behav Neurosci 2016 1;10:103. Epub 2016 Jun 1.

Department of Neuroscience, Innsbruck Medical University Innsbruck, Austria.

The presence of the p75 neurotrophin receptor (p75NTR) in adult basal forebrain cholinergic neurons, precursor cells in the subventricular cell layer and the subgranular cell layer of the hippocampus has been linked to alterations in learning as well as anxiety- and depression- related behaviors. In contrast to previous studies performed in a p75NTR(exon III-/-) model still expressing the short isoform of the p75NTR, we focused on locomotor and anxiety-associated behavior in p75NTR(exon IV-/-) mice lacking both p75NTR isoforms. Comparing p75NTR(exon IV-/-) and wildtype mice for both male and female animals showed an anxiolytic-like behavior as evidenced by increased central activities in the open field paradigm and flex field activity system as well as higher numbers of open arm entries in the elevated plus maze test in female p75NTR knockout mice. Morphometrical analyses of dorsal and ventral hippocampus revealed a reduction of width of the dentate gyrus and the granular cell layer in the dorsal but not ventral hippocampus in male and female p75NTR(exon IV-/-) mice. We conclude that germ-line deletion of p75NTR seems to differentially affect morphometry of dorsal and ventral dentate gyrus and that p75NTR may play a role in anxiety-like behavior, specifically in female mice.
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http://dx.doi.org/10.3389/fnbeh.2016.00103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4887477PMC
June 2016

Social interaction reward decreases p38 activation in the nucleus accumbens shell of rats.

Neuropharmacology 2015 Dec 20;99:510-6. Epub 2015 Aug 20.

Experimental Psychiatry Unit, Medical University of Innsbruck, Innsbruck, Austria. Electronic address:

We have previously shown that animals acquired robust conditioned place preference (CPP) to either social interaction alone or cocaine alone. Recently it has been reported that drugs of abuse abnormally activated p38, a member of mitogen-activated protein kinase family, in the nucleus accumbens. In this study, we aimed to investigate the expression of the activated form of p38 (pp38) in the nucleus accumbens shell and core of rats expressing either cocaine CPP or social interaction CPP 1 h, 2 h and 24 h after the CPP test. We hypothesized that cocaine CPP will increase pp38 in the nucleus accumbens shell/core as compared to social interaction CPP. Surprisingly, we found that 24 h after social interaction CPP, pp38 neuronal levels were decreased in the nucleus accumbens shell to the level of naïve rats. Control saline rats that received saline in both compartments of the CPP apparatus and cocaine CPP rats showed similar enhanced p38 activation as compared to naïve and social interaction CPP rats. We also found that the percentage of neurons expressing dopaminergic receptor D2R and pp38 was also decreased in the shell of the nucleus accumbens of social interaction CPP rats as compared to controls. Given the emerging role of p38 in stress/anxiety behaviors, these results suggest that (1) social interaction reward has anti-stress effects; (2) cocaine conditioning per se does not affect p38 activation and that (3) marginal stress is sufficient to induce p38 activation in the shell of the nucleus accumbens.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5056637PMC
http://dx.doi.org/10.1016/j.neuropharm.2015.08.029DOI Listing
December 2015

Alternative generation of CNS neural stem cells and PNS derivatives from neural crest-derived peripheral stem cells.

Stem Cells 2015 Feb;33(2):574-88

Max-Planck-Institute for Brain Research, Research Group Developmental Neurobiology, Frankfurt, Germany.

Neural crest-derived stem cells (NCSCs) from the embryonic peripheral nervous system (PNS) can be reprogrammed in neurosphere (NS) culture to rNCSCs that produce central nervous system (CNS) progeny, including myelinating oligodendrocytes. Using global gene expression analysis we now demonstrate that rNCSCs completely lose their previous PNS characteristics and acquire the identity of neural stem cells derived from embryonic spinal cord. Reprogramming proceeds rapidly and results in a homogenous population of Olig2-, Sox3-, and Lex-positive CNS stem cells. Low-level expression of pluripotency inducing genes Oct4, Nanog, and Klf4 argues against a transient pluripotent state during reprogramming. The acquisition of CNS properties is prevented in the presence of BMP4 (BMP NCSCs) as shown by marker gene expression and the potential to produce PNS neurons and glia. In addition, genes characteristic for mesenchymal and perivascular progenitors are expressed, which suggests that BMP NCSCs are directed toward a pericyte progenitor/mesenchymal stem cell (MSC) fate. Adult NCSCs from mouse palate, an easily accessible source of adult NCSCs, display strikingly similar properties. They do not generate cells with CNS characteristics but lose the neural crest markers Sox10 and p75 and produce MSC-like cells. These findings show that embryonic NCSCs acquire a full CNS identity in NS culture. In contrast, MSC-like cells are generated from BMP NCSCs and pNCSCs, which reveals that postmigratory NCSCs are a source for MSC-like cells up to the adult stage.
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http://dx.doi.org/10.1002/stem.1880DOI Listing
February 2015

Reacquisition of cocaine conditioned place preference and its inhibition by previous social interaction preferentially affect D1-medium spiny neurons in the accumbens corridor.

Front Behav Neurosci 2014 24;8:317. Epub 2014 Sep 24.

Experimental Psychiatry Unit, Innsbruck Medical University Innsbruck, Austria ; Department of Psychology, Leopold-Franzens University of Innsbruck Innsbruck, Austria.

We investigated if counterconditioning with dyadic (i.e., one-to-one) social interaction, a strong inhibitor of the subsequent reacquisition of cocaine conditioned place preference (CPP), differentially modulates the activity of the diverse brain regions oriented along a mediolateral corridor reaching from the interhemispheric sulcus to the anterior commissure, i.e., the nucleus of the vertical limb of the diagonal band, the medial septal nucleus, the major island of Calleja, the intermediate part of the lateral septal nucleus, and the medial accumbens shell and core. We also investigated the involvement of the lateral accumbens core and the dorsal caudate putamen. The anterior cingulate 1 (Cg1) region served as a negative control. Contrary to our expectations, we found that all regions of the accumbens corridor showed increased expression of the early growth response protein 1 (EGR1, Zif268) in rats 2 h after reacquisition of CPP for cocaine after a history of cocaine CPP acquisition and extinction. Previous counterconditioning with dyadic social interaction inhibited both the reacquisition of cocaine CPP and the activation of the whole accumbens corridor. EGR1 activation was predominantly found in dynorphin-labeled cells, i.e., presumably D1 receptor-expressing medium spiny neurons (D1-MSNs), with D2-MSNs (immunolabeled with an anti-DRD2 antibody) being less affected. Cholinergic interneurons or GABAergic interneurons positive for parvalbumin, neuropeptide Y or calretinin were not involved in these CPP-related EGR1 changes. Glial cells did not show any EGR1 expression either. The present findings could be of relevance for the therapy of impaired social interaction in substance use disorders, depression, psychosis, and autism spectrum disorders.
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http://dx.doi.org/10.3389/fnbeh.2014.00317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4174134PMC
October 2014

Peripheral nerve regeneration and NGF-dependent neurite outgrowth of adult sensory neurons converge on STAT3 phosphorylation downstream of neuropoietic cytokine receptor gp130.

J Neurosci 2014 Sep;34(39):13222-33

Divisions of Physiology, and

After nerve injury, adult sensory neurons can regenerate peripheral axons and reconnect with their target tissue. Initiation of outgrowth, as well as elongation of neurites over long distances, depends on the signaling of receptors for neurotrophic growth factors. Here, we investigated the importance of gp130, the signaling subunit of neuropoietic cytokine receptors in peripheral nerve regeneration. After sciatic nerve crush, functional recovery in vivo was retarded in SNS-gp130(-/-) mice, which specifically lack gp130 in sensory neurons. Correspondingly, a significantly reduced number of free nerve endings was detected in glabrous skin from SNS-gp130(-/-) compared with control mice after nerve crush. Neurite outgrowth and STAT3 activation in vitro were severely reduced in cultures in gp130-deficient cultured neurons. Surprisingly, in neurons obtained from SNS-gp130(-/-) mice the increase in neurite length was reduced not only in response to neuropoietic cytokine ligands of gp130 but also to nerve growth factor (NGF), which does not bind to gp130-containing receptors. Neurite outgrowth in the absence of neurotrophic factors was partially rescued in gp130-deficient neurons by leptin, which activates STAT3 downstream of leptic receptor and independent of gp130. The neurite outgrowth response of gp130-deficient neurons to NGF was fully restored in the presence of leptin. Based on these findings, gp130 signaling via STAT3 activation is suggested not only to be an important regulator of peripheral nerve regeneration in vitro and in vivo, but as determining factor for the growth promoting action of NGF in adult sensory neurons.
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http://dx.doi.org/10.1523/JNEUROSCI.1209-13.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4172810PMC
September 2014

Induced pluripotent stem cells from friedreich ataxia patients fail to upregulate frataxin during in vitro differentiation to peripheral sensory neurons.

Stem Cells Dev 2013 Dec 24;22(24):3271-82. Epub 2013 Aug 24.

1 Department of Neurology, Innsbruck Medical University , Innsbruck, Austria .

The value of human disease models, which are based on induced pluripotent stem cells (iPSCs), depends on the capacity to generate specifically those cell types affected by pathology. We describe a new iPSC-based model of Friedreich ataxia (FRDA), an autosomal recessive neurodegenerative disorder with an intronic GAA repeat expansion in the frataxin gene. As the peripheral sensory neurons are particularly susceptible to neurodegeneration in FRDA, we applied a development-based differentiation protocol to generate specifically these cells. FRDA and control iPSC lines were efficiently differentiated toward neural crest progenitors and peripheral sensory neurons. The progress of the cell lines through discrete steps of in vitro differentiation was closely monitored by expression levels of key markers for peripheral neural development. Since it had been suggested that FRDA pathology might start early during ontogenesis, we investigated frataxin expression in our development-related model. A pronounced frataxin deficit was found in FRDA iPSCs and neural crest cells compared to controls. Whereas we identified an upregulation of frataxin expression during sensory specification for control cells, this increase was not observed for FRDA peripheral sensory neurons. This early failure, aggravating frataxin deficiency in a specifically vulnerable human cell population, indicates a developmental component in FRDA.
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http://dx.doi.org/10.1089/scd.2013.0126DOI Listing
December 2013

Cell fate analysis of embryonic ventral mesencephalic grafts in the 6-OHDA model of Parkinson's disease.

PLoS One 2012 29;7(11):e50178. Epub 2012 Nov 29.

Division of Neurobiology, Department of Neurology, Medical University Innsbruck, Innsbruck, Austria.

Evidence from carefully conducted open label clinical trials suggested that therapeutic benefit can be achieved by grafting fetal dopaminergic (DAergic) neurons derived from ventral mesencephalon (VM) into the denervated striatum of Parkinson's disease (PD) patients. However, two double-blind trials generated negative results reporting deleterious side effects such as prominent dyskinesias. Heterogeneous composition of VM grafts is likely to account for suboptimal clinical efficacy.We consider that gene expression patterns of the VM tissue needs to be better understood by comparing the genetic signature of the surviving and functioning grafts with the cell suspensions used for transplantation. In addition, it is crucial to assess whether the grafted cells exhibit the DAergic phenotype of adult substantia nigra pars compacta (SNpc). To investigate this further, we used a GFP reporter mouse as source of VM tissue that enabled the detection and dissection of the grafts 6 weeks post implantation. A comparative gene expression analysis of the VM cell suspension and grafts revealed that VM grafts continue to differentiate post-implantation. In addition, implanted grafts showed a mature SNpc-like molecular DAergic phenotype with similar expression levels of TH, Vmat2 and Dat. However, by comparing gene expression of the adult SNpc with dissected grafts we detected a higher expression of progenitor markers in the grafts. Finally, when compared to the VM cell suspension, post-grafting there was a higher expression of markers inherent to glia and other neuronal populations.In summary, our data highlight the dynamic development of distinctive DAergic and non-DAergic gene expression markers associated with the maturation of VM grafts in vivo. The molecular signature of VM grafts and its functional relevance should be further explored in future studies aimed at the optimization of DAergic cell therapy approaches in PD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0050178PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3510255PMC
June 2013

Acetylcholine, drug reward and substance use disorder treatment: intra- and interindividual striatal and accumbal neuron ensemble heterogeneity may explain apparent discrepant findings.

Pharmacology 2012 25;90(5-6):264-73. Epub 2012 Sep 25.

Experimental Psychiatry Unit, Innsbruck Medical University, Innsbruck, Austria.

Converging evidence from different independent laboratories suggests that acetylcholine may play an important role in drug reward and that modulation of the cholinergic system may be useful for the treatment of substance use disorders. In this commentary, we try to reconcile apparently discrepant animal behavioral, human behavioral and clinical data with a unifying hypothesis positing that the modulation of drug-versus natural stimuli-mediated reward by cholinergic interneurons in the nucleus accumbens (and the dorsal striatum) is restricted to distinct neuron ensembles that show considerable intra- and interindividual variation with respect to their spatial distribution. The precise targeting of these interindividually variable neuron ensembles would be a prerequisite for a successful pharmacotherapy based on the modulation of the cholinergic system. We also provide experimental data to support our unifying hypothesis.
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http://dx.doi.org/10.1159/000342636DOI Listing
April 2013

Brain regions associated with the acquisition of conditioned place preference for cocaine vs. social interaction.

Front Behav Neurosci 2012 24;6:63. Epub 2012 Sep 24.

Experimental Psychiatry Unit, Medical University Innsbruck Innsbruck, Austria.

Positive social interaction could play an essential role in switching the preference of the substance dependent individual away from drug related activities. We have previously shown that conditioned place preference (CPP) for cocaine at the dose of 15 mg/kg and CPP for four 15-min episodes of social interaction were equally strong when rats were concurrently conditioned for place preference by pairing cocaine with one compartment and social interaction with the other. The aim of the present study was to investigate the differential activation of brain regions related to the reward circuitry after acquisition/expression of cocaine CPP or social interaction CPP. Our findings indicate that cocaine CPP and social interaction CPP activated almost the same brain regions. However, the granular insular cortex and the dorsal part of the agranular insular cortex were more activated after cocaine CPP, whereas the prelimbic cortex and the core subregion of the nucleus accumbens were more activated after social interaction CPP. These results suggest that the insular cortex appears to be potently activated after drug conditioning learning while activation of the prelimbic cortex-nucleus accumbens core projection seems to be preferentially involved in the conditioning to non-drug stimuli such as social interaction.
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http://dx.doi.org/10.3389/fnbeh.2012.00063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3449336PMC
October 2012

Expression of early developmental markers predicts the efficiency of embryonic stem cell differentiation into midbrain dopaminergic neurons.

Stem Cells Dev 2013 Feb 20;22(3):397-411. Epub 2012 Sep 20.

Institute for Neuroscience, Innsbruck Medical University, Innsbruck, Austria.

Dopaminergic neurons derived from pluripotent stem cells are among the best investigated products of in vitro stem cell differentiation owing to their potential use for neurorestorative therapy of Parkinson's disease. However, the classical differentiation protocols for both mouse and human pluripotent stem cells generate a limited percentage of dopaminergic neurons and yield a considerable cellular heterogeneity comprising numerous scarcely characterized cell populations. To improve pluripotent stem cell differentiation protocols for midbrain dopaminergic neurons, we established extensive and strictly quantitative gene expression profiles, including markers for pluripotent cells, neural progenitors, non-neural cells, pan-neuronal and glial cells, neurotransmitter phenotypes, midbrain and nonmidbrain populations, floor plate and basal plate populations, as well as for Hedgehog, Fgf, and Wnt signaling pathways. The profiles were applied to discrete stages of in vitro differentiation of mouse embryonic stem cells toward the dopaminergic lineage and after transplantation into the striatum of 6-hydroxy-dopamine-lesioned rats. The comparison of gene expression in vitro with stages in the developing ventral midbrain between embryonic day 11.5 and 13.5 ex vivo revealed dynamic changes in the expression of transcription factors and signaling molecules. Based on these profiles, we propose quantitative gene expression milestones that predict the efficiency of dopaminergic differentiation achieved at the end point of the protocol, already at earlier stages of differentiation.
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http://dx.doi.org/10.1089/scd.2012.0238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549628PMC
February 2013

Identification of differentially expressed non-coding RNAs in embryonic stem cell neural differentiation.

Nucleic Acids Res 2012 Jul 6;40(13):6001-15. Epub 2012 Apr 6.

Division of Genomics and RNomics, Biocenter, Medical University Innsbruck, Innrain 80/82, A-6020 Innsbruck, Austria.

Protein-coding genes, guiding differentiation of ES cells into neural cells, have extensively been studied in the past. However, for the class of ncRNAs only the involvement of some specific microRNAs (miRNAs) has been described. Thus, to characterize the entire small non-coding RNA (ncRNA) transcriptome, involved in the differentiation of mouse ES cells into neural cells, we have generated three specialized ribonucleo-protein particle (RNP)-derived cDNA libraries, i.e. from pluripotent ES cells, neural progenitors and differentiated neural cells, respectively. By high-throughput sequencing and transcriptional profiling we identified several novel miRNAs to be involved in ES cell differentiation, as well as seven small nucleolar RNAs. In addition, expression of 7SL, 7SK and vault-2 RNAs was significantly up-regulated during ES cell differentiation. About half of ncRNA sequences from the three cDNA libraries mapped to intergenic or intragenic regions, designated as interRNAs and intraRNAs, respectively. Thereby, novel ncRNA candidates exhibited a predominant size of 18-30 nt, thus resembling miRNA species, but, with few exceptions, lacking canonical miRNA features. Additionally, these novel intraRNAs and interRNAs were not only found to be differentially expressed in stem-cell derivatives, but also in primary cultures of hippocampal neurons and astrocytes, strengthening their potential function in neural ES cell differentiation.
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http://dx.doi.org/10.1093/nar/gks311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3401476PMC
July 2012

Preventive role of social interaction for cocaine conditioned place preference: correlation with FosB/DeltaFosB and pCREB expression in rat mesocorticolimbic areas.

Front Behav Neurosci 2012 2;6. Epub 2012 Mar 2.

Experimental Psychiatry Unit, Center for Psychiatry and Psychotherapy, Medical University Innsbruck Innsbruck, Austria.

The worsening of drug abuse by drug-associated social interaction is a well-studied phenomenon. In contrast, the molecular mechanisms of the beneficial effect of social interaction, if offered as a mutually exclusive choice to drugs of abuse, are under-investigated. In a rat place preference conditioning (CPP) paradigm, four 15 min episodes of social interaction with a gender- and weight-matched male early-adult conspecific inhibited cocaine-induced reinstatement of cocaine CPP, a model of relapse. These protective effects of social interaction were paralleled by a reduced activation, as assessed by Zif268 expression, in brain areas known to play pivotal roles in drug-seeking behavior. Here we show that social interaction during extinction of cocaine CPP also reduced cocaine-CPP-stimulated FosB expression in the nucleus accumbens shell and core. In addition, social interaction during cocaine CPP extinction increased pCREB (cAMP response element binding protein) expression in the nucleus accumbens shell and the cingulate cortex area 1 (Cg1). Our results show that FosB and pCREB may be implicated in the protective effect of social interaction against cocaine-induced reinstatement of CPP. Thus, social interaction, if offered in a context that is clearly distinct from the previously drug-associated one, may profoundly inhibit relapse to cocaine addiction.
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http://dx.doi.org/10.3389/fnbeh.2012.00008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3291868PMC
October 2012

Pharmacological modulation of the Hedgehog pathway differentially affects dorsal/ventral patterning in mouse and human embryonic stem cell models of telencephalic development.

Stem Cells Dev 2012 May 8;21(7):1016-46. Epub 2012 Feb 8.

Institute for Neuroscience, Innsbruck Medical University, Innsbruck, Austria.

A complex set of extrinsic and intrinsic signals acts in specific temporal and spatial orders to enable neural differentiation during development. These processes have been extensively studied in animal models, but human neural development remains much less understood. This lack of detailed information about human early neurogenesis is a hindrance for the differentiation of pluripotent stem cell lines into specific neuronal phenotypes. Therefore, it is important to strengthen the interspecies comparative approaches. We describe a novel model system in which in vitro differentiation of human and mouse embryonic stem (ES) cells are temporally aligned to each other and compared with mouse telencephalic neurogenesis in vivo. In this comparative model system, we tested the in vitro role of Hedgehog (Hh) signaling for ES cell-derived telencephalic differentiation. In vivo, Hh signaling mediates dorsal/ventral patterning during early stages of telencephalic development. We monitored the effect of pharmacological modulators of the Hh signaling pathway, purmorphamine-an agonist and cyclopamine-an antagonist of the Smoothened receptor (Smo), on the expression of region-specific transcription factors and signaling molecules relevant for telencephalic development in vivo. Purmorphamine strongly upregulated the expression of telencephalic ventral markers Nkx2.1, Nkx6.2, Lhx6, and Lhx8 in mouse and human cells, thus reflecting the in vivo process of the medial ganglionic eminence patterning and specification. Cyclopamine upregulated the expression of telencephalic dorsal markers, but at lower levels in human compared with mouse cells. Modulation of Smo in vitro differentially affected, in mouse and human cells, the expression of molecules of the Hh pathway, especially the Gli1 and Gli3 effectors, Sonic Hh ligand and Ptch receptors. These results provide evidence for the different default differentiation of mouse and human ES cells and prove the utility of the comparative system for optimizing the directed differentiation of human pluripotent stem cells.
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http://dx.doi.org/10.1089/scd.2011.0271DOI Listing
May 2012

p38α and p38β mitogen-activated protein kinases determine cholinergic transdifferentiation of sympathetic neurons.

J Neurosci 2011 Aug;31(34):12059-67

Institute for Neuroscience, Innsbruck Medical University, MZA, 6020 Innsbruck, Austria.

Although the p38 mitogen-activated protein kinases are active in many neuronal populations in the peripheral and central nervous systems, little is known about the physiological functions of p38 in postmitotic neurons. We report that p38 activity determines in vitro and in vivo the switch from noradrenergic to cholinergic neurotransmission that occurs in sympathetic neurons on exposure to the neuropoietic cytokines CNTF and LIF. This transdifferentiation serves as a model for the plastic mechanisms that enable mature neurons to change some of their central functions without passing through the cell cycle. We demonstrate that in postmitotic neurons, p38 and STAT pathways are concurrently activated by neuropoietic cytokine treatment for at least 12 h overlapping with changes in neurotransmitter marker gene expression. Inhibition of p38 blocks the upregulation of the nuclear matrix protein Satb2 and of cholinergic markers by CNTF without affecting STAT3 phosphorylation. Conversely, overexpression of p38α or β in the absence of cytokines stimulates cholinergic marker expression. The neurotransmitter switch in vitro is impaired in neurons isolated from p38β(-/-) mice. Consistent with these in vitro results, a substantial loss of cells expressing cholinergic properties is observed in vivo in the stellate ganglion of mature mice deficient in the p38β isoform.
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http://dx.doi.org/10.1523/JNEUROSCI.0448-11.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6623226PMC
August 2011

Reversal of cocaine-conditioned place preference and mesocorticolimbic Zif268 expression by social interaction in rats.

Addict Biol 2011 Apr 11;16(2):273-84. Epub 2011 Feb 11.

Experimental Psychiatry Unit, Medical University Innsbruck, Innrain 66a, A-6020 Innsbruck, Austria.

Little is known how social interaction, if offered as an alternative to drug consumption, affects neural circuits involved in drug reinforcement and substance dependence. Conditioned place preference (CPP) for cocaine (15 mg/kg i.p.) or social interaction (15 minutes) as an alternative stimulus was investigated in male Sprague-Dawley rats. Four social interaction episodes with a male adult conspecific completely reversed cocaine CPP and were even able to prevent reacquisition of cocaine CPP. Social interaction also reversed cocaine CPP-induced expression of the immediate-early gene zif268 in the nucleus accumbens shell, the central and basolateral amygdala and the ventral tegmental area. These findings suggest that social interaction, if offered in a context that is clearly distinct from the previously drug-associated ones, may profoundly decrease the incentive salience of drug-associated contextual stimuli. The novel experimental design facilitates the neurobiological investigation of this phenomenon which may be beneficial for human drug users in treatment.
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http://dx.doi.org/10.1111/j.1369-1600.2010.00285.xDOI Listing
April 2011

Milestones of directed differentiation of mouse and human embryonic stem cells into telencephalic neurons based on neural development in vivo.

Stem Cells Dev 2011 Jun 31;20(6):947-58. Epub 2011 Jan 31.

Department of Cellular and Molecular Medicine, University of Medicine and Pharmacy Carol Davila, Bucharest, Romania.

Understanding the normal development of individual neural subtypes provides an essential framework for the design of rational approaches to embryonic stem cell differentiation for in vitro studies and cell replacement therapies. Of particular interest and a particular challenge are the cells that build-up the telencephalon. Recent research has unraveled key developmental mechanisms contributing to the generation of specific telencephalic cells. We focus on morphogens and transcription factors known to regulate distinct developmental processes. These include early anterior/posterior patterning, dorsal/ventral patterning, and generation of progenitor domains and neuronal specification into major classes of telencephalic cells: glutamatergic projection neurons, different subtypes of γ-aminobutyric acid-ergic interneurons and projection neurons, as well as cholinergic interneurons and projection neurons. Based on a comparison with in vivo telencephalic neurogenesis, we propose that the specific combinations of transcription factors expressed during development can serve as milestones for the in vitro differentiation of embryonic stem cells toward specific telencephalic neurons.
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http://dx.doi.org/10.1089/scd.2010.0417DOI Listing
June 2011

The sympathetic neurotransmitter switch depends on the nuclear matrix protein Satb2.

J Neurosci 2010 Dec;30(48):16356-64

Institute for Neuroscience, Innsbruck Medical University, 6020 Innsbruck, Austria.

Sympathetic neurons can switch their neurotransmitter phenotype from noradrenergic to cholinergic on exposure to neuropoietic cytokines in vitro and in vivo. Here, we provide evidence that this transspecification is regulated by the chromatin architecture protein Satb2. Treatment with the neuropoietic cytokines ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor rapidly and strongly increases Satb2 transcript and protein levels in cultures of rat superior cervical ganglia neurons. Knockdown of endogenous Satb2 by short interfering RNA prevents the upregulation of choline acetyltransferase (Chat) and vesicular acetylcholine transporter (Vacht) by CNTF as well as the loss of norepinephrine transporter (Net). Conversely, overexpression of Satb2 in the noradrenergic sympathetic phenotype results in a marked increase of Chat and Vacht expression and reduced Net mRNA levels in the absence of neuropoietic cytokines. Chromatin immunoprecipitation analysis in primary sympathetic neurons reveals that Satb2 binds to matrix attachment regions (MARs) within the Chat locus. In vivo, in the rat stellate ganglion, Satb2 is expressed exclusively in sudomotor cholinergic neurons innervating the sweat glands and only after establishment of contact between neurons and target. These findings demonstrate a function of the MAR-binding protein Satb2 in growth factor-dependent neurotransmitter plasticity in postmitotic neurons.
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http://dx.doi.org/10.1523/JNEUROSCI.3502-10.2010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6634850PMC
December 2010

Development of neurotransmitter phenotypes in sympathetic neurons.

Auton Neurosci 2009 Nov 5;151(1):30-8. Epub 2009 Sep 5.

Institute for Neuroscience, Innsbruck Medical University, MZA, Austria.

This review summarizes the current understanding of neurotransmitter phenotype specification of postganglionic sympathetic neurons, focusing, in particular, on the cellular processes of induction versus trans-differentiation. The emerging evidence is discussed that the noradrenergic and cholinergic neurotransmitter phenotypes are co-induced during early development and that the mature phenotypes develop by positive and negative selection of cellular properties in initially bimodal neurons, depending on extracellular signals during migration and after target contact.
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http://dx.doi.org/10.1016/j.autneu.2009.08.012DOI Listing
November 2009

Striatal transplantation in a rodent model of multiple system atrophy: effects on L-Dopa response.

J Neurosci Res 2009 May;87(7):1679-85

Section for Clinical Neurobiology, Innsbruck Medical University, Innsbruck, Austria.

Progressive degeneration of striatal projection neurons is thought to account for the loss of L-Dopa response observed in the majority of patients with the parkinsonian variant of multiple system atrophy (MSA-P). Here we have investigated the effects of E14 embryonic striatal allografts on dopaminergic responsiveness in the unilateral double-lesion rat model of MSA-P by using tests of complex motor behavior. Both sham and graft animals showed an increase in apomorphine-induced rotations as well as an improvement in cylinder test performance following surgical intervention. In contrast, L-Dopa responsiveness of stepping behavior was improved only in grafted animals. The restoration of apomorphine-induced rotation correlated with the P-zone volume of grafts. Our findings indicate that transplantation of embryonic striatal grafts might, at least to some extent, restore responsiveness to L-Dopa in tasks of complex motor behavior. Therefore, striatal transplantation should be further defined preclinically as a possible therapeutic option for patients with MSA-P and a failing L-Dopa response.
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http://dx.doi.org/10.1002/jnr.21972DOI Listing
May 2009

The rabies virus glycoprotein receptor p75NTR is not essential for rabies virus infection.

J Virol 2007 Dec 10;81(24):13622-30. Epub 2007 Oct 10.

Laboratoire de Virologie Moléculaire et Structurale, UMR 2472 CNRS-INRA, CNRS, 91198 Gif-sur-Yvette Cedex, France.

Rabies virus glycoprotein (RVG) is known to be the only factor that mediates rabies infection. The neurotrophin receptor (p75(NTR)), through its cysteine-rich domain 1, is a specific receptor for RVG and neutralizes virus infectivity, but its role in virus infection has remained obscure. We used adult mouse dorsal root ganglion (DRG) neurons as a model to study the role of p75(NTR) in RV infection of primary neurons. We show that RV infects around 20% of DRG neurons, of which more than 80% are p75(NTR) positive, have large diameters, and are capsaicin insensitive. Surprisingly, RV binding and infection are absent in about half of the p75(NTR)-expressing DRG neurons which have small diameters and are often capsaicin sensitive. This indicates that p75(NTR) is not sufficient to mediate RV interaction in sensory neurons. The rate and specificity of neural infection are unchanged in RV-infected p75(NTRExonIV-/-) mice that lack all extracellular receptor domains and in wild-type mice infected with two independent RV mutants that lack p75(NTR) binding. Accordingly, the mortality rate is unchanged in the absence of RV-p75(NTR) interaction. We conclude that although p75(NTR) is a receptor for soluble RVG in transfected cells of heterologous expression systems, an RVG-p75(NTR) interaction is not necessary for RV infection of primary neurons. This means that other receptors are required to mediate RV infection in vivo and in vitro.
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http://dx.doi.org/10.1128/JVI.02368-06DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2168826PMC
December 2007

Neurotransmitter phenotype-specific expression changes in developing sympathetic neurons.

Mol Cell Neurosci 2007 Jul 1;35(3):397-408. Epub 2007 Apr 1.

Institute for Neuroscience, Innsbruck Medical University, MZA, Anichstrasse 35, 6020 Innsbruck, Austria.

During late developmental phases individual sympathetic neurons undergo a switch from noradrenergic to cholinergic neurotransmission. This phenomenon of plasticity depends on target-derived signals in vivo and is triggered by neurotrophic factors in neuronal cultures. To analyze genome-wide expression differences between the two transmitter phenotypes we employed DNA microarrays. RNA expression profiles were obtained from chick paravertebral sympathetic ganglia, treated with neurotrophin 3, glial cell line-derived neurotrophic factor or ciliary neurotrophic factor, all of which stimulate cholinergic differentiation. Results were compared with the effect of nerve growth factor, which functions as a pro-noradrenergic stimulus. The gene set common to all three comparisons defined the noradrenergic and cholinergic synexpression groups. Several functional categories, such as signal transduction, G-protein-coupled signaling, cation transport, neurogenesis and synaptic transmission, were enriched in these groups. Experiments based on the prediction that some of the identified genes play a role in the neurotransmitter switch identified bone morphogenetic protein signaling as an inhibitor of cholinergic differentiation.
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http://dx.doi.org/10.1016/j.mcn.2007.03.014DOI Listing
July 2007

Neurotrophic factors acutely alter the sorting of the vesicular acetyl choline transporter and the vesicular monoamine transporter 2 in bimodal sympathetic neurons.

Mol Cell Neurosci 2007 Jan 23;34(1):1-9. Epub 2006 Oct 23.

Institute for Neuroscience, Innsbruck Medical University, MZA, Anichstr. 35, 6020 Innsbruck, Austria.

Individual sympathetic neurons in co-cultures with cardiac myocytes store acetylcholine and noradrenaline in two different populations of synaptic vesicles and release both neurotransmitters from single presynaptic terminals. Neurotrophic factors selectively and acutely stimulate differential release of the two types of neurotransmitters from these bimodal neurons. Here we investigated the acute effects of neurotrophic factors on two pivotal marker proteins for catecholaminergic and cholinergic synaptic vesicle populations: the vesicular monoamine transporter 2 and the vesicular acetylcholine transporter. We observed that separation of the two fluorescence labeled transporters is not restricted to the varicosities, but can also be observed in the neurites as well as in the cell soma. Application of nerve growth factor, brain-derived neurotrophic factor and ciliary neuronotrophic factor caused acute alterations in transporter segregation. These results point to a novel function of neurotrophic factors during the short-term regulation of synaptic protein sorting in neurons.
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http://dx.doi.org/10.1016/j.mcn.2006.09.005DOI Listing
January 2007