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  • 1.
    Alsiö, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Nordenankar, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Arvidsson, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Birgner, Carolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Mahmoudi, Souha
    Halbout, Briac
    Smith, Casey
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Fortin, Guillaume M.
    Olson, Lars
    Descarries, Laurent
    Trudeau, Louis-Eric
    Kullander, Klas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Levesque, Daniel
    Wallén-Mackenzie, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Enhanced Sucrose and Cocaine Self-Administration and Cue-Induced Drug Seeking after Loss of VGLUT2 in Midbrain Dopamine Neurons in Mice2011In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 31, no 35, p. 12593-12603Article in journal (Refereed)
    Abstract [en]

    The mesostriatal dopamine (DA) system contributes to several aspects of responses to rewarding substances and is implicated in conditions such as drug addiction and eating disorders. A subset of DA neurons has been shown to express the type 2 Vesicular glutamate transporter (Vglut2) and may therefore corelease glutamate. In the present study, we analyzed mice with a conditional deletion of Vglut2 in DA neurons (Vglut2(f/f;DAT-Cre)) to address the functional significance of the glutamate-DA cophenotype for responses to cocaine and food reinforcement. Biochemical parameters of striatal DA function were also examined by using DA receptor autoradiography, immediate-early gene quantitative in situ hybridization after cocaine challenge, and DA-selective in vivo chronoamperometry. Mice in which Vglut2 expression had been abrogated in DA neurons displayed enhanced operant self-administration of both high-sucrose food and intravenous cocaine. Furthermore, cocaine seeking maintained by drug-paired cues was increased by 76%, showing that reward-dependent plasticity is perturbed in these mice. In addition, several lines of evidence suggest that adaptive changes occurred in both the ventral and dorsal striatum in the absence of VGLUT2: DA receptor binding was increased, and basal mRNA levels of the DA-induced early genes Nur77 and c-fos were elevated as after cocaine induction. Furthermore, in vivo challenge of the DA system by potassium-evoked depolarization revealed less DA release in both striatal areas. This study demonstrates that absence of VGLUT2 in DA neurons leads to perturbations of reward consumption as well as reward-associated memory, features of particular relevance for addictive-like behavior.

  • 2. Andersson, M
    et al.
    Konradi, C
    Cenci, M A
    cAMP response element-binding protein is required for dopamine-dependent gene expression in the intact but not the dopamine-denervated striatum.2001In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 21, no 24, p. 9930-43Article in journal (Refereed)
    Abstract [en]

    The cAMP response element-binding protein (CREB) is believed to play a pivotal role in dopamine (DA) receptor-mediated nuclear signaling and neuroplasticity. Here we demonstrate that the significance of CREB for gene expression depends on the experimental paradigm. We compared the role of CREB in two different but related models: l-DOPA administration to unilaterally 6-hydroxydopamine lesioned rats, and cocaine administration to neurologically intact animals. Antisense technology was used to produce a local knockdown of CREB in the lateral caudate-putamen, a region that mediates the dyskinetic or stereotypic manifestations associated with l-DOPA or cocaine treatment, respectively. In intact rats, CREB antisense reduced both basal and cocaine-induced expression of c-Fos, FosB/DeltaFosB, and prodynorphin mRNA. In the DA-denervated striatum, CREB was not required for l-DOPA to induce these gene products, nor did CREB contribute considerably to DNA binding activity at cAMP responsive elements (CREs) and CRE-like enhancers. DeltaFosB-related proteins and JunD were the main contributors to both CRE and AP-1 DNA-protein complexes in l-DOPA-treated animals. In behavioral studies, intrastriatal CREB knockdown caused enhanced activity scores in intact control animals and exacerbated the dyskinetic effects of acute l-DOPA treatment in 6-OHDA-lesioned animals. These data demonstrate that CREB is not required for the development of l-DOPA-induced dyskinesia in hemiparkinsonian rats. Moreover, our results reveal an unexpected alteration of nuclear signaling mechanisms in the parkinsonian striatum treated with l-DOPA, where AP-1 transcription factors appear to supersede CREB in the activation of CRE-containing genes.

  • 3. Bedford, Lynn
    et al.
    Hay, David
    Devoy, Anny
    Paine, Simon
    Powe, Des G
    Seth, Rashmi
    Gray, Trevor
    Topham, Ian
    Fone, Kevin
    Rezvani, Nooshin
    Mee, Maureen
    Soane, Tim
    Layfield, Robert
    Sheppard, Paul W
    Ebendal, Ted
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Usoskin, Dmitry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Lowe, James
    Mayer, R John
    Depletion of 26S proteasomes in mouse brain neurons causes neurodegeneration and Lewy-like inclusions resembling human pale bodies2008In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 28, no 33, p. 8189-98Article in journal (Refereed)
    Abstract [en]

    Ubiquitin-positive intraneuronal inclusions are a consistent feature of the major human neurodegenerative diseases, suggesting that dysfunction of the ubiquitin proteasome system is central to disease etiology. Research using inhibitors of the 20S proteasome to model Parkinson's disease is controversial. We report for the first time that specifically 26S proteasomal dysfunction is sufficient to trigger neurodegenerative disease. Here, we describe novel conditional genetic mouse models using the Cre/loxP system to spatially restrict inactivation of Psmc1 (Rpt2/S4) to neurons of either the substantia nigra or forebrain (e.g., cortex, hippocampus, and striatum). PSMC1 is an essential subunit of the 26S proteasome and Psmc1 conditional knock-out mice display 26S proteasome depletion in targeted neurons, in which the 20S proteasome is not affected. Impairment of specifically ubiquitin-mediated protein degradation caused intraneuronal Lewy-like inclusions and extensive neurodegeneration in the nigrostriatal pathway and forebrain regions. Ubiquitin and alpha-synuclein neuropathology was evident, similar to human Lewy bodies, but interestingly, inclusion bodies contained mitochondria. We support this observation by demonstrating mitochondria in an early form of Lewy body (pale body) from Parkinson's disease patients. The results directly confirm that 26S dysfunction in neurons is involved in the pathology of neurodegenerative disease. The model demonstrates that 26S proteasomes are necessary for normal neuronal homeostasis and that 20S proteasome activity is insufficient for neuronal survival. Finally, we are providing the first reproducible genetic platform for identifying new therapeutic targets to slow or prevent neurodegeneration.

  • 4.
    Bolzon, Douglas M
    et al.
    University of Adelaide.
    Nordström, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    O'Carroll, David C
    Local and large-range inhibition in feature detection2009In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 29, no 45, p. 14143-14150Article in journal (Refereed)
    Abstract [en]

    Lateral inhibition is perhaps the most ubiquitous of neuronal mechanisms, having been demonstrated in early stages of processing in many different sensory pathways of both mammals and invertebrates. Recent work challenges the long-standing view that assumes that similar mechanisms operate to tune neuronal responses to higher order properties. Scant evidence for lateral inhibition exists beyond the level of the most peripheral stages of visual processing, leading to suggestions that many features of the tuning of higher order visual neurons can be accounted for by the receptive field and other intrinsic coding properties of visual neurons. Using insect target neurons as a model, we present unequivocal evidence that feature tuning is shaped not by intrinsic properties but by potent spatial lateral inhibition operating well beyond the first stages of visual processing. In addition, we present evidence for a second form of higher-order spatial inhibition--a long-range interocular transfer of information that we argue serves a role in establishing interocular rivalry and thus potentially a neural substrate for directing attention to single targets in the presence of distracters. In so doing, we demonstrate not just one, but two levels of spatial inhibition acting beyond the level of peripheral processing.

  • 5. Borgegård, Tomas
    et al.
    Gustavsson, Susanne
    Nilsson, Charlotte
    Parpal, Santiago
    Klintenberg, Rebecka
    Berg, Anna-Lena
    Rosqvist, Susanne
    Serneels, Lutgarde
    Svensson, Samuel
    Olsson, Fredrik
    Jin, Shaobo
    Yan, Hongmei
    Wanngren, Johanna
    Jureus, Anders
    Ridderstad-Wollberg, Anna
    Wollberg, Patrik
    Stockling, Kenneth
    Karlström, Helena
    Malmberg, Asa
    Lund, Johan
    Arvidsson, Per I
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    De Strooper, Bart
    Lendahl, Urban
    Lundkvist, Johan
    Alzheimer's Disease: Presenilin 2-Sparing γ-Secretase Inhibition Is a Tolerable Aβ Peptide-Lowering Strategy2012In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 32, no 48, p. 17297-17305Article in journal (Refereed)
    Abstract [en]

    γ-Secretase inhibition represents a major therapeutic strategy for lowering amyloid β (Aβ) peptide production in Alzheimer's disease (AD). Progress toward clinical use of γ-secretase inhibitors has, however, been hampered due to mechanism-based adverse events, primarily related to impairment of Notch signaling. The γ-secretase inhibitor MRK-560 represents an exception as it is largely tolerable in vivo despite displaying only a small selectivity between Aβ production and Notch signaling in vitro. In exploring the molecular basis for the observed tolerability, we show that MRK-560 displays a strong preference for the presenilin 1 (PS1) over PS2 subclass of γ-secretases and is tolerable in wild-type mice but causes dose-dependent Notch-related side effect in PS2-deficient mice at drug exposure levels resulting in a substantial decrease in brain Aβ levels. This demonstrates that PS2 plays an important role in mediating essential Notch signaling in several peripheral organs during pharmacological inhibition of PS1 and provide preclinical in vivo proof of concept for PS2-sparing inhibition as a novel, tolerable and efficacious γ-secretase targeting strategy for AD.

  • 6.
    de Haan, Roel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Lee, Yu-Jen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Nordström, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Novel Flicker-Sensitive Visual Circuit Neurons Inhibited by Stationary Patterns2013In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 33, no 21, p. 8980-8989Article in journal (Refereed)
    Abstract [en]

    Many animals use visual motion cues for navigating within their surroundings. Both flies and vertebrates compute local motion by temporal correlation of neighboring photoreceptors, via so-called elementary motion detectors (EMDs). In the fly lobula plate and the vertebrate visual cortex the output from many EMDs is pooled in neurons sensitive to wide-field optic flow. Although the EMD has been the preferred model for more than 50 years, recent work has highlighted its limitations in describing some visual behaviors, such as responses to higher-order motion stimuli. Non-EMD motion processing may therefore serve an important function in vision. Here, we describe a novel neuron class in the fly lobula plate that clearly does not derive its input from classic EMDs. The centrifugal stationary inhibited flicker excited (cSIFE) neuron is strongly excited by flicker, up to very high temporal frequencies. The non-EMD driven flicker sensitivity leads to strong, nondirectional responses to high-speed, wide-field motion. Furthermore, cSIFE is strongly inhibited by stationary patterns, within a narrow wavelength band. cSIFE's outputs overlap with the inputs of well described optic flow-sensitive lobula plate tangential cells (LPTCs). Driving cSIFE affects the active dendrites of LPTCs, and cSIFE may therefore play a large role in motion vision.

  • 7. Diogenes, Maria Jose
    et al.
    Dias, Raquel B.
    Rombo, Diogo M.
    Miranda, Hugo Vicente
    Maiolino, Francesca
    Guerreiro, Patricia
    Näsström, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Franquelim, Henri G.
    Oliveira, Luis M. A.
    Castanho, Miguel A. R. B.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Bergström, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Quintas, Alexandre
    Sebastiao, Ana M.
    Lopes, Luisa V.
    Outeiro, Tiago Fleming
    Extracellular Alpha-Synuclein Oligomers Modulate Synaptic Transmission and Impair LTP Via NMDA-Receptor Activation2012In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 32, no 34, p. 11750-11762Article in journal (Refereed)
    Abstract [en]

    Parkinson's disease (PD) is the most common representative of a group of disorders known as synucleinopathies, in which misfolding and aggregation of alpha-synuclein (a-syn) in various brain regions is the major pathological hallmark. Indeed, the motor symptoms in PD are caused by a heterogeneous degeneration of brain neurons not only in substantia nigra pars compacta but also in other extrastriatal areas of the brain. In addition to the well known motor dysfunction in PD patients, cognitive deficits and memory impairment are also an important part of the disorder, probably due to disruption of synaptic transmission and plasticity in extrastriatal areas, including the hippocampus. Here, we investigated the impact of a-syn aggregation on AMPA and NMDA receptor-mediated rat hippocampal (CA3-CA1) synaptic transmission and long-term potentiation (LTP), the neurophysiological basis for learning and memory. Our data show that prolonged exposure to a-syn oligomers, but not monomers or fibrils, increases basal synaptic transmission through NMDA receptor activation, triggering enhanced contribution of calcium-permeable AMPA receptors. Slices treated with a-syn oligomers were unable to respond with further potentiation to theta-burst stimulation, leading to impaired LTP. Prior delivery of a low-frequency train reinstated the ability to express LTP, implying that exposure to a-syn oligomers drives the increase of glutamatergic synaptic transmission, preventing further potentiation by physiological stimuli. Our novel findings provide mechanistic insight on how a-syn oligomers may trigger neuronal dysfunction and toxicity in PD and other synucleinopathies.

  • 8.
    Enjin, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Perry, Sharn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Hilscher, Markus M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Nagaraja, Chetan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Larhammar, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Gezelius, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Eriksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Leão, Katarina E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Kullander, Klas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Developmental disruption of recurrent inhibitory feedback results in compensatory adaptation in the Renshaw cell-motor neuron circuit2017In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 37, no 23, p. 5634-5647Article in journal (Refereed)
    Abstract [en]

    When activating muscles, motor neurons in the spinal cord also activate Renshaw cells, which provide recurrent inhibitory feedback to the motor neurons. The tight coupling with motor neurons suggests that Renshaw cells have an integral role in movement, a role that is yet to be elucidated. Here we used the selective expression of the nicotinic cholinergic receptor α2 (Chrna2) in mice to genetically target the vesicular inhibitory amino acid transporter (VIAAT) in Renshaw cells. Loss of VIAAT from Chrna2Cre-expressing Renshaw cells did not impact any aspect of drug-induced fictive locomotion in the neonatal mouse or change gait, motor coordination, or grip strength in adult mice of both sexes. However, motor neurons from neonatal mice lacking VIAAT in Renshaw cells received spontaneous inhibitory synaptic input with a reduced frequency, showed lower input resistance, and had an increased number of proprioceptive glutamatergic and calbindin-labeled putative Renshaw cell synapses on their soma and proximal dendrites. Concomitantly, Renshaw cells developed with increased excitability and a normal number of cholinergic motor neuron synapses, indicating a compensatory mechanism within the recurrent inhibitory feedback circuit. Our data suggest an integral role for Renshaw cell signaling in shaping the excitability and synaptic input to motor neurons.

  • 9.
    Erlandsson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Enarsson, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Forsberg-Nilsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Immature neurons from CNS stem cells proliferate in response toplatelet-derived growth factor2001In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 21, no 10, p. 3483-3491Article in journal (Refereed)
    Abstract [en]

    Identifying external signals involved in the regulation of neural stem cell proliferation and differentiation is fundamental to the understanding of CNS development. In this study we show that platelet-derived growth factor (PDGF) can act as a mitogen for neural precursor cells. Multipotent stem cells from developing CNS can be maintained in a proliferative state under serum-free conditions in the presence of fibroblast growth factor-2 (FGF2) and induced to differentiate into neurons, astrocytes, and oligodendrocytes on withdrawal of the mitogen. PDGF has been suggested to play a role during the differentiation into neurons. We have investigated the effect of PDGF on cultured stem cells from embryonic rat cortex. The PDGF alpha-receptor is constantly expressed during differentiation of neural stem cells but is phosphorylated only after PDGF-AA treatment. In contrast, the PDGF beta-receptor is hardly detectable in uncommitted cells, but its expression increases during differentiation. We show that PDGF stimulation leads to c-fos induction, 5'-bromo-2'deoxyuridine incorporation, and an increase in the number of immature cells stained with antibodies to neuronal markers. Our findings suggest that PDGF acts as a mitogen in the early phase of stem cell differentiation to expand the pool of immature neurons.

  • 10. Fieblinger, Tim
    et al.
    Sebastianutto, Irene
    Alcacer, Cristina
    Bimpisidis, Zisis
    Maslava, Natallia
    Sandberg, Sabina
    Engblom, David
    Cenci, Maria Angela
    Mechanisms of Dopamine D1 Receptor-Mediated ERK1/2 Activation in the Parkinsonian Striatum and Their Modulation by Metabotropic Glutamate Receptor Type 52014In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 34, p. 4778-4740Article in journal (Refereed)
  • 11. Fortin, G. M.
    et al.
    Bourque, M. -J
    Mendez, J. A.
    Leo, D.
    Nordenankar, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Birgner, Carolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Arvidsson, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Rymar, V. V.
    Bérubé-Carriére, N.
    Claveau, A. -M
    Descarries, L.
    Sadikot, A. F.
    Mackenzie, Åsa Wallén
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Trudeau, L. -E
    Glutamate corelease promotes growth and survival of midbrain dopamine neurons2012In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 32, no 48, p. 17477-17491Article in journal (Refereed)
    Abstract [en]

    Recent studies have proposed that glutamate corelease by mesostriatal dopamine (DA) neurons regulates behavioral activation by psychostimulants.How and when glutamate release by DA neurons might play this role remains unclear. Considering evidence for early expression of the type 2 vesicular glutamate transporter in mesencephalic DA neurons, we hypothesized that this cophenotype is particularly important during development. Using a conditional gene knock-out approach to selectively disrupt the Vglut2 gene in mouse DA neurons, we obtained in vitro and in vivo evidence for reduced growth and survival of mesencephalic DA neurons, associated with a decrease in the density of DA innervation in the nucleus accumbens, reduced activity-dependent DA release, and impaired motor behavior. These findings provide strong evidence for a functional role of the glutamatergic cophenotype in the development of mesencephalic DA neurons, opening new perspectives into the pathophysiology of neurodegenerative disorders involving the mesostriatal DA system.

  • 12. Furmark, Tomas
    et al.
    Appel, Lieuwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Henningsson, Susanne
    Ahs, Fredrik
    Faria, Vanda
    Linnman, Clas
    Pissiota, Anna
    Frans, Orjan
    Bani, Massimo
    Bettica, Paolo
    Pich, Emilio Merlo
    Jacobsson, Eva
    Wahlstedt, Kurt
    Oreland, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Långström, Bengt
    Eriksson, Elias
    Fredrikson, Mats
    A link between serotonin-related gene polymorphisms, amygdala activity, and placebo-induced relief from social anxiety2008In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 28, no 49, p. 13066-74Article in journal (Refereed)
    Abstract [en]

    Placebo may yield beneficial effects that are indistinguishable from those of active medication, but the factors underlying proneness to respond to placebo are widely unknown. Here, we used functional neuroimaging to examine neural correlates of anxiety reduction resulting from sustained placebo treatment under randomized double-blind conditions, in patients with social anxiety disorder. Brain activity was assessed during a stressful public speaking task by means of positron emission tomography before and after an 8 week treatment period. Patients were genotyped with respect to the serotonin transporter-linked polymorphic region (5-HTTLPR) and the G-703T polymorphism in the tryptophan hydroxylase-2 (TPH2) gene promoter. Results showed that placebo response was accompanied by reduced stress-related activity in the amygdala, a brain region crucial for emotional processing. However, attenuated amygdala activity was demonstrable only in subjects who were homozygous for the long allele of the 5-HTTLPR or the G variant of the TPH2 G-703T polymorphism, and not in carriers of short or T alleles. Moreover, the TPH2 polymorphism was a significant predictor of clinical placebo response, homozygosity for the G allele being associated with greater improvement in anxiety symptoms. Path analysis supported that the genetic effect on symptomatic improvement with placebo is mediated by its effect on amygdala activity. Hence, our study shows, for the first time, evidence of a link between genetically controlled serotonergic modulation of amygdala activity and placebo-induced anxiety relief.

  • 13.
    Furmark, Tomas
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Åhs, Fredrik
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Faria, Vanda
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Linnman, Clas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Pissiota, Anna
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Frans, Örjan
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Fredrikson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    A Link between Serotonin-Related Gene Polymorphisms, Amygdala Activity, and Placebo-Induced Relief from Social Anxiety2008In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 28, no 49Article in journal (Refereed)
    Abstract [en]

    Placebo may yield beneficial effects that are indistinguishable from those of active medication, but the factors underlying proneness to respond to placebo are widely unknown. Here, we used functional neuroimaging to examine neural correlates of anxiety reduction resulting from sustained placebo treatment under randomized double-blind conditions, in patients with social anxiety disorder. Brain activity was assessed during a stressful public speaking task by means of positron emission tomography before and after an 8 week treatment period. Patients were genotyped with respect to the serotonin transporter-linked polymorphic region (5-HTTLPR) and the G-703T polymorphism in the tryptophan hydroxylase-2 (TPH2) gene promoter. Results showed that placebo response was accompanied by reduced stress-related activity in the amygdala, a brain region crucial for emotional processing. However, attenuated amygdala activity was demonstrable only in subjects who were homozygous for the long allele of the 5-HTTLPR or the G variant of the TPH2 G-703T polymorphism, and not in carriers of short or T alleles. Moreover, the TPH2 polymorphism was a significant predictor of clinical placebo response, homozygosity for the G allele being associated with greater improvement in anxiety symptoms. Path analysis supported that the genetic effect on symptomatic improvement with placebo is mediated by its effect on amygdala activity. Hence, our study shows, for the first time, evidence of a link between genetically controlled serotonergic modulation of amygdala activity and placebo-induced anxiety relief.

  • 14.
    Hallböök, Finn
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Lundin, Lars-Gustav
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kullander, Klas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Lampetra fluviatilis neurotrophin homolog, descendant of a neurotrophin ancestor, discloses the early molecular evolution of neurotrophins in the vertebrate subphylum1998In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 18, no 21, p. 8700-8711Article in journal (Refereed)
    Abstract [en]

    We have isolated a neurotrophin from the lamprey that permitted us to perform a phylogenetic analysis of the neurotrophin gene family that dates back more than 460 million years to the early vertebrate ancestors. The results show that the neurotrophin gene family was originally formed by two subsequent duplications. The duplication that formed nerve growth factor, neurotrophin-3, brain-derived neurotrophic factor, and neurotrophin-4/5 occurred after the split of lampreys but before the split of cartilaginous fish from the main vertebrate lineage. Compilation of chromosomal gene maps around the neurotrophins shows that they are located in paralogous regions, suggesting that the genes were formed at major duplication events possibly by complete genome doubling. Analysis of two isolated Trk receptor sequences shows similar results as for the lamprey neurotrophin. Multiple neurotrophin and Trk genes, including neurotrophin-6 and -7, have been found in bony fish, and we suggest that the extra genes were formed by an additional duplication in the bony fish lineage. Analysis of lamprey Trk mRNA expression in the adult brain shows that the genes are expressed in all regions analyzed so far. Together, the results suggest that the duplications of ancestral neurotrophin and Trk genes at an early vertebrate stage have permitted evolution to bring about differential neurotrophin and Trk expression, thereby allowing the formation of specific functions in selective neuronal populations.

  • 15. Jakobsson, Joel
    et al.
    Ackermann, Frauke
    Andersson, Fredrik
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Löw, Peter
    Brodin, Lennart
    Regulation of Synaptic Vesicle Budding and Dynamin Function by an EHD ATPase2011In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 31, no 39, p. 13972-13980Article in journal (Refereed)
    Abstract [en]

    Eps15 homology domain-containing proteins (EHDs) are conserved ATPases implicated in membrane remodeling. Recently, EHD1 was found to be enriched at synaptic release sites, suggesting a possible involvement in the trafficking of synaptic vesicles. We have investigated the role of an EHD1/3 ortholog (1-EHD) in the lamprey giant reticulospinal synapse. 1-EHD was detected by immunogold at endocytic structures adjacent to release sites. In antibody microinjection experiments, perturbation of 1-EHD inhibited synaptic vesicle endocytosis and caused accumulation of clathrin-coated pits with atypical, elongated necks. The necks were covered with helix-like material containing dynamin. To test whether 1-EHD directly interferes with dynamin function, we used fluid-supported bilayers as in vitro assay. We found that 1-EHD strongly inhibited vesicle budding induced by dynamin in the constant presence of GTP. 1-EHD also inhibited dynamin-induced membrane tubulation in the presence of GTP gamma S, a phenomenon linked with dynamin helix assembly. Our in vivo results demonstrate the involvement of 1-EHD in clathrin/dynamin-dependent synaptic vesicle budding. Based on our in vitro observations, we suggest that 1-EHD acts to limit the formation of long, unproductive dynamin helices, thereby promoting vesicle budding.

  • 16. Kadison, Stephanie R
    et al.
    Mäkinen, Taija
    Klein, Rüdiger
    Henkemeyer, Mark
    Kaprielian, Zaven
    EphB receptors and ephrin-B3 regulate axon guidance at the ventral midline of the embryonic mouse spinal cord.2006In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 26, no 35Article in journal (Refereed)
    Abstract [en]

    EphB receptors and their ephrin-B ligands are required for midline guidance decisions at several rostrocaudal levels of the developing CNS. In the embryonic vertebrate spinal cord, ephrin-B3 is localized to the floor plate (FP) at the ventral midline (VM), ephrin-B1 and ephrin-B2 are expressed in the dorsal spinal cord, and decussated EphB receptor-bearing commissural axons navigate between these ventral and dorsal ephrin-B domains. Despite these compelling expression patterns, the in vivo role(s) for EphB and ephrin-B proteins in regulating the guidance of spinal commissural axons has not been established. Here, we use DiI (1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate) labeling to assess the pathfinding of commissural axons in the spinal cords of ephrin-B and EphB mutant mouse embryos. In mice lacking ephrin-B3 or multiple EphB receptors, a significant number of axons followed aberrant trajectories in the immediate vicinity of the VM. Furthermore, forked transverse commissural (FTC) axons, a unique class of commissural axons that continues to project in the transverse plane on the contralateral side of the FP, were present at a markedly higher frequency in ephrin-B3 and EphB mutants, compared with wild-type embryos. Neither the midline guidance errors nor excessive numbers of FTC axons were observed in the spinal cords of ephrin-B3(lacz) mice that express a truncated form of ephrin-B3, which is capable of forward but not reverse signaling. In contrast to the midline guidance defects observed in EphB and ephrin-B3 mutant embryos, wild-type-like contralateral projections were observed in mice lacking ephrin-B1 and/or ephrin-B2.

  • 17.
    Krieger, Patrik
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Kuner, Thomas
    Sakmann, Bert
    Synaptic connections between layer 5B pyramidal neurons in mouse somatosensory cortex are independent of apical dendrite bundling2007In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 27, no 43, p. 11473-11482Article in journal (Refereed)
    Abstract [en]

    Rodent somatosensory barrel cortex is organized both physiologically and anatomically in columns with a cross-sectional diameter of 100-400 mu m. The underlying anatomical correlate of physiologically defined, much narrower minicolumns (20-60 mu m in diameter) remains unclear. The minicolumn has been proposed to be a fundamental functional unit in the cortex, and one anatomical component of a minicolumn is thought to be a cluster of pyramidal cells in layer 5B (L5B) that contribute their apical dendrite to distinct bundles. In transgenic mice with fluorescently labeled L5B pyramidal cells, which project to the pons and thalamus, we investigated whether the pyramidal cells of a cluster also share functional properties. We found that apical dendrite bundles in the transgenic mice were anatomically similar to apical dendrite bundles previously proposed to be part of minicolumns. We made targeted whole-cell recordings in acute brain slices from pairs of fluorescently labeled L5B pyramidal cells that were located either in the same cluster or in adjacent clusters and subsequently reconstructed their dendritic arbors. Pyramids within the same cluster had larger common dendritic domains compared with pyramids in adjacent clusters but did not receive more correlated synaptic inputs. L5B pyramids within and between clusters have similar connection probabilities and unitary EPSP amplitudes. Furthermore, intrinsically bursting and regular spiking pyramidal cells were both present within the same cluster. In conclusion, intrinsic electrical excitability and the properties of synaptic connections between this subtype of L5B pyramidal cells are independent of the cell clusters defined by bundling of their apical dendrites.

  • 18.
    Lindberg, Nanna
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Jiang, Yiwen
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Xie, Yuan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Bolouri, Hamid
    Kastemar, Marianne
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Olofsson, Tommie
    Holland, Eric C.
    Uhrbom, Lene
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Oncogenic Signaling Is Dominant to Cell of Origin and Dictates Astrocytic or Oligodendroglial Tumor Development from Oligodendrocyte Precursor Cells2014In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 34, no 44, p. 14644-14651Article in journal (Refereed)
    Abstract [en]

    Stem cells, believed to be the cellular origin of glioma, are able to generate gliomas, according to experimental studies. Here we investigated the potential and circumstances of more differentiated cells to generate glioma development. We and others have shown that oligodendrocyte precursor cells (OPCs) can also be the cell of origin for experimental oligodendroglial tumors. However, the question of whether OPCs have the capacity to initiate astrocytic gliomas remains unanswered. Astrocytic and oligodendroglial tumors represent the two most common groups of glioma and have been considered as distinct disease groups with putatively different origins. Here we show that mouse OPCs can give rise to both types of glioma given the right circumstances. We analyzed tumors induced by K-RAS and AKT and compared them to oligodendroglial platelet-derived growth factor B-induced tumors in Ctv-a mice with targeted deletions of Cdkn2a (p16(Ink4a-/-), p19(Arf-/-), Cdkn2a(-/-)). Our results showed that glioma can originate from OPCs through overexpression of K-RAS and AKT when combined with p19(Arf) loss, and these tumors displayed an astrocytic histology and high expression of astrocytic markers. We argue that OPC shave the potential to develop both astrocytic and oligodendroglial tumors given loss of p19(Arf), and that oncogenic signaling is dominant to cell of origin in determining glioma phenotype. Our mouse data are supported by the fact that human astrocytoma and oligodendroglioma display a high degree of overlap in global gene expression with no clear distinctions between the two diagnoses.

  • 19. Näsman, Johnny
    et al.
    Bart, Genevieve
    Larsson, Kim
    Louhivuori, Lauri
    Peltonen, Hanna
    Åkerman, Karl E. O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    The orexin OX1 receptor regulates Ca2+ entry via diacylglycerol-activated channels in differentiated neuroblastoma cells2006In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 26, no 42, p. 10658-10666Article in journal (Refereed)
    Abstract [en]

    We studied the cellular response to orexin type 1 receptor (OX1R) stimulation in differentiated IMR-32 neuroblastoma cells. In vitro differentiation of IMR-32 cells with 5-bromo-2'-deoxyuridine leads to a neuronal phenotype with long neurite extensions and an upregulation of mainly N-type voltage-gated calcium channels. Transduction of differentiated IMR-32 cells with baculovirus harboring an OX1R-green fluorescent protein cDNA fusion construct resulted in appearance of fluorescence that was confined mainly to the plasma membrane in the cell body and to neurites. Application of orexin-A to fluorescent cells led to an increase in intracellular free Ca2+ concentration, [Ca2+](i). At low nanomolar concentrations of orexin-A, the response was reversibly attenuated by removal of extracellular Ca2+, by application of a high concentration (10 mM) of Mg2+, and by the pharmacological channel blocker dextromethorphan. A diacylglycerol, dioctanoylglycerol, but not thapsigargin or depolarization with potassium, mimicked the OX1R response with regard to Mg2+ sensitivity. A reverse transcription-PCR screening identified mRNAs for all transient receptor potential canonical (TRPC) channels, including TRPC3, TRPC6, and TRPC7, which are known to be activated by diacylglycerol. Expression of a dominant-negative TRPC6 channel subunit blunted the responses to both dioctanoylglycerol and OX1R stimulation. The results suggest that the OX1R activates a Ca2+ entry pathway that involves diacylglycerol-activated TRPC channels in neuronal cells.

  • 20.
    Ossipov, Michael H.
    et al.
    Department of Pharmacology, University of Arizona Health Sciences Center, Tucson, Arizona 85724.
    Bazov, Igor
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm S-17176, Sweden.
    Gardell, Luis R.
    Department of Pharmacology, University of Arizona Health Sciences Center, Tucson, Arizona 85724.
    Kowal, Justin
    Department of Pharmacology, University of Arizona Health Sciences Center, Tucson, Arizona 85724.
    Yakovleva, Tatiana
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm S-17176, Sweden.
    Usynin, Ivan
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm S-17176, Sweden.
    Ekström, Tomas J.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm S-17176, Sweden.
    Porreca, Frank
    Department of Pharmacology, University of Arizona Health Sciences Center, Tucson, Arizona 85724.
    Bakalkin, Georgy
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm S-17176, Sweden.
    Control of chronic pain by the ubiquitin-proteasome system in the spinal cord2007In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 27, no 31, p. 8226-37Article in journal (Refereed)
    Abstract [en]

    Chronic pain is maintained in part by long-lasting neuroplastic changes in synapses and several proteins critical for synaptic plasticity are degraded by the ubiquitin-proteasome system (UPS). Here, we show that proteasome inhibitors administered intrathecally or subcutaneously prevented the development and reversed nerve injury-induced pain behavior. They also blocked pathological pain induced by sustained administration of morphine or spinal injection of dynorphin A, an endogenous mediator of chronic pain. Proteasome inhibitors blocked mechanical allodynia and thermal hyperalgesia in all three pain models although they did not modify responses to mechanical stimuli, but partially inhibited responses to thermal stimuli in control rats. In the spinal cord, these compounds abolished the enhanced capsaicin-evoked calcitonin gene-related peptide (CGRP) release and dynorphin A upregulation, both elicited by nerve injury. Model experiments demonstrated that the inhibitors may act directly on dynorphin-producing cells, blocking dynorphin secretion. Thus, the effects of proteasome inhibitors on chronic pain were apparently mediated through several cellular mechanisms indispensable for chronic pain, including those of dynorphin A release and postsynaptic actions, and of CGRP secretion. Levels of several UPS proteins were reduced in animals with neuropathic pain, suggesting that UPS downregulation, like effects of proteasome inhibitors, counteracts the development of chronic pain. The inhibitors did not produce marked or disabling motor disturbances at doses that were used to modify chronic pain. These results suggest that the UPS is a critical intracellular regulator of pathological pain, and that UPS-mediated protein degradation is required for maintenance of chronic pain and nociceptive, but not non-nociceptive responses in normal animals.

  • 21.
    Rabe, Nadine
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Gezelius, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Vallstedt, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Memic, Fatima
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Kullander, Klas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Netrin-1-Dependent Spinal Interneuron Subtypes Are Required for the Formation of Left-Right Alternating Locomotor Circuitry2009In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 29, no 50, p. 15642-15649Article in journal (Refereed)
    Abstract [en]

    Neuronal circuits in the spinal cord that produce the rhythmic and coordinated activities necessary for limb movements are referred to as locomotor central pattern generators (CPGs). The identities and preceding development of neurons essential for coordination between left and right limbs are not yet known. We show that the ventral floor plate chemoattractant Netrin-1 preferentially guides dorsally originating subtypes of commissural interneurons, the majority of which are inhibitory. In contrast, the excitatory and ventralmost V3 subtype of interneurons have a normal number of commissural fibers in Netrin-1 mutant mice, thus being entirely independent of Netrin-1-mediated attraction. This selective loss of commissural fibers in Netrin-1 mutant mice resulted in an abnormal circuitry manifested by a complete switch from alternating to synchronous fictive locomotor activity suggesting that the most ventral-originating excitatory commissural interneurons are an important component of a left-right synchrony circuit in the locomotor CPG. Thus, during development, Netrin-1 plays a critical role for the establishment of a functional balanced CPG.

  • 22.
    Rogóz, Katarzyna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Andersen, Helena H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Lagerström, Malin C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Kullander, Klas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Multimodal Use of Calcitonin Gene-Related Peptide and Substance P in Itch and Acute Pain Uncovered by the Elimination of Vesicular Glutamate Transporter 2 from Transient Receptor Potential Cation Channel Subfamily V Member 1 Neurons2014In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 34, no 42, p. 14055-14068Article in journal (Refereed)
    Abstract [en]

    Primary afferents are known to use glutamate as their principal fast neurotransmitter. However, it has become increasingly clear that peptides have an influential role in both mediating and modulating sensory transmission. Here we describe the transmission accounting for different acute pain states and itch transmitted via the transient receptor potential cation channel subfamily V member 1 (TRPV1) population by either ablating Trpv1-Cre-expressing neurons or inducing vesicular glutamate transporter 2 (VGLUT2) deficiency in Trpv1-Cre-expressing neurons. Furthermore, by pharmacological inhibition of substance P or calcitonin gene-related peptide (CGRP) signaling in Vglut2-deficient mice, we evaluated the contribution of substance P or CGRP to these sensory modulations, with or without the presence of VGLUT2-mediated glutamatergic transmission in Trpv1-Cre neurons. This examination, together with c-Fos analyses, showed that glutamate via VGLUT2 in the Trpv1-Cre population together with substance P mediate acute cold pain, whereas glutamate together with CGRP mediate noxious heat. Moreover, we demonstrate that glutamate together with both substance P and CGRP mediate tissue-injury associated pain. We further show that itch, regulated by the VGLUT2-mediated transmission via the Trpv1-Cre population, depends on CGRP and gastrin-releasing peptide receptor (GRPR) transmission because pharmacological blockade of the CGRP or GRPR pathway, or genetic ablation of Grpr, led to a drastically attenuated itch. Our study reveals how different neurotransmitters combined can cooperate with each other to transmit or regulate various acute sensations, including itch.

  • 23.
    Rostami, Jinar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Holmqvist, Staffan
    Lund Univ, Wallenberg Neurosci Ctr, Stem Cell Lab CNS Dis Modeling, Dept Expt Med Sci, S-22184 Lund, Sweden.;Lund Univ, Strateg Res Area MultiPk, S-22184 Lund, Sweden.;Lund Univ, Lund Stem Cell Ctr, S-22184 Lund, Sweden..
    Lindström, Veronica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Sigvardson, Jessica
    BioArctic AB, S-11251 Stockholm, Sweden..
    Westermark, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Bergström, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Roybon, Laurent
    Lund Univ, Wallenberg Neurosci Ctr, Stem Cell Lab CNS Dis Modeling, Dept Expt Med Sci, S-22184 Lund, Sweden.;Lund Univ, Strateg Res Area MultiPk, S-22184 Lund, Sweden.;Lund Univ, Lund Stem Cell Ctr, S-22184 Lund, Sweden..
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Human Astrocytes Transfer Aggregated Alpha-Synuclein via Tunneling Nanotubes2017In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 37, no 49, p. 11835-11853Article in journal (Refereed)
    Abstract [en]

    Many lines of evidence suggest that the Parkinson's disease (PD)-related protein alpha-synuclein (alpha-SYN) can propagate from cell to cell in a prion-like manner. However, the cellular mechanisms behind the spreading remain elusive. Here, we show that human astrocytes derived from embryonic stem cells actively transfer aggregated alpha-SYN to nearby astrocytes via direct contact and tunneling nanotubes (TNTs). Failure in the astrocytes' lysosomal digestion of excess alpha-SYN oligomers results in alpha-SYN deposits in the trans-Golgi network followed by endoplasmic reticulum swelling and mitochondrial disturbances. The stressed astrocytes respond by conspicuously sending out TNTs, enabling intercellular transfer of alpha-SYN to healthy astrocytes, which in return deliver mitochondria, indicating a TNT-mediated rescue mechanism. Using a pharmacological approach to inhibit TNT formation, we abolished the transfer of both alpha-SYN and mitochondria. Together, our results highlight the role of astrocytes in alpha-SYN cell-to-cell transfer, identifying possible pathophysiological events in the PD brain that could be of therapeutic relevance.

  • 24. Serradj, Najet
    et al.
    Paixao, Sonia
    Sobocki, Tomasz
    Feinberg, Mitchell
    Klein, Ruediger
    Kullander, Klas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Martin, John H.
    EphA4-Mediated Ipsilateral Corticospinal Tract Misprojections Are Necessary for Bilateral Voluntary Movements But Not Bilateral Stereotypic Locomotion2014In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 34, no 15, p. 5211-5221Article in journal (Refereed)
    Abstract [en]

    In this study, we took advantage of the reported role of EphA4 in determining the contralateral spinal projection of the corticospinal tract (CST) to investigate the effects of ipsilateral misprojections on voluntary movements and stereotypic locomotion. Null EphA4 mutations produce robust ipsilateral CST misprojections, resulting in bilateral corticospinal tracts. We hypothesize that a unilateral voluntary limb movement, not a stereotypic locomotor movement, will become a bilateral movement in EphA4 knock-out mice with a bilateral CST. However, in EphA4 full knock-outs, spinal interneurons also develop bilateral misprojections. Aberrant bilateral spinal circuits could thus transform unilateral corticospinal control signals into bilateral movements. We therefore studied mice with conditional forebrain deletion of the EphA4 gene under control by Emx1, a gene expressed in the forebrain that affects the developing CST but spares brainstem motor pathways and spinal motor circuits. We examined two conditional knock-outs targeting forebrain EphA4 during performance of stereotypic locomotion and voluntary movement: adaptive locomotion over obstacles and exploratory reaching. We found that the conditional knock-outs used alternate stepping, not hopping, during overground locomotion, suggesting normal central pattern generator function and supporting our hypothesis of minimal CST involvement in the moment-to-moment control of stereotypic locomotion. In contrast, the conditional knock-outs showed bilateral voluntary movements under conditions when single limb movements are normally produced and, as a basis for this aberrant control, developed a bilateral motor map in motor cortex that is driven by the aberrant ipsilateral CST misprojections. Therefore, a specific change in CST connectivity is associated with and explains a change in voluntary movement.

  • 25. Sokka, Anna-Leena
    et al.
    Putkonen, Noora
    Mudo, Giuseppa
    Pryazhnikov, Evgeny
    Reijonen, Sami
    Khiroug, Leonard
    Belluardo, Natale
    Lindholm, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Korhonen, Laura
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Endoplasmic Reticulum Stress Inhibition Protects against Excitotoxic Neuronal Injury in the Rat Brain2007In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 27, no 4, p. 901-908Article in journal (Refereed)
    Abstract [en]

    Elevated brain glutamate with activation of neuronal glutamate receptors accompanies neurological disorders, such as epilepsy and brain trauma. However, the mechanisms by which excitotoxicity triggers neuronal injury are not fully understood. We have studied the glutamate receptor agonist kainic acid (KA) inducing seizures and excitotoxic cell death. KA caused the disintegration of the endoplasmic reticulum (ER) membrane in hippocampal neurons and ER stress with the activation of the ER proteins Bip, Chop, and caspase-12. Salubrinal, inhibiting eIF2α (eukaryotic translation initiation factor 2 subunit α) dephosphorylation, significantly reduced KA-induced ERstress and neuronal death in vivo and in vitro. KA-induced rise in intracellular calcium was not affected by Salubrinal. The results show that ER responses are essential parts of excitotoxicity mediated by glutamate receptor activation and that Salubrinal decreases neuronal death in vivo. Inhibition of ER stress by small molecular compounds may be beneficial for treatment of various neuronal injuries and brain disorders.

  • 26. Volakakis, Nikolaos
    et al.
    Tiklova, Katarina
    Decressac, Mickeal
    Papathanou, Maria
    Mattsson, Bengt
    Gillberg, Linda
    Nobre, Andre
    Björklund, Anders
    Perlmann, Thomas
    Nurr1 and Retinoid X Receptor Ligands Stimulate Ret Signaling in Dopamine Neurons and Can Alleviate α-Synuclein Disrupted Gene Expression2015In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 35, no 42, p. 14370-14385Article in journal (Refereed)
    Abstract [en]

    α-synuclein, a protein enriched in Lewy bodies and highly implicated in neurotoxicity in Parkinson's disease, is distributed both at nerve terminals and in the cell nucleus. Here we show that a nuclear derivative of α-synuclein induces more pronounced changes at the gene expression level in mouse primary dopamine (DA) neurons compared to a derivative that is excluded from the nucleus. Moreover, by RNA sequencing we analyzed the extent of genome-wide effects on gene expression resulting from expression of human α-synuclein in primary mouse DA neurons. The results implicated the transcription factor Nurr1 as a key dysregulated target of α-synuclein toxicity. Forced Nurr1 expression restored the expression of hundreds of dysregulated genes in primary DA neurons expressing α-synuclein, and therefore prompted us to test the possibility that Nurr1 can be pharmacologically targeted by bexarotene, a ligand for the retinoid X receptor that forms heterodimers with Nurr1. Although our data demonstrated that bexarotene was ineffective in neuroprotection in rats in vivo, the results revealed that bexarotene has the capacity to coregulate subsets of Nurr1 target genes including the receptor tyrosine kinase subunit Ret. Moreover, bexarotene was able to restore dysfunctional Ret-dependent neurotrophic signaling in α-synuclein-overexpressing mouse DA neurons. These data highlight the role of the Nurr1-Ret signaling pathway as a target of α-synuclein toxicity and suggest that retinoid X receptor ligands with appropriate pharmacological properties could have therapeutic potential in Parkinson's disease.

  • 27. Wallis, Karin
    et al.
    Sjögren, Maria
    van Hogerlinden, Max
    Silberberg, Gilad
    Fisahn, André
    Nordström, Kristina
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Westerblad, Håkan
    Morreale de Escobar, Gabriela
    Shupliakov, Oleg
    Vennström, Björn
    Locomotor deficiencies and aberrant development of subtype-specific GABAergic interneuros caused by a unlignded thyroid hormopne receptor alpha-12008In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 28, no 8, p. 1904-1915Article in journal (Refereed)
    Abstract [en]

    Thyroid hormone (TH) deficiency during development causes severe and permanent neuronal damage, but the primary insult at the tissue level has remained unsolved. We have defined locomotor deficiencies in mice caused by a mutant thyroid hormone receptor alpha 1 (TR alpha 1) with potent aporeceptor activity attributable to reduced affinity to TH. This allowed identification of distinct functions that required either maternal supply of TH during early embryonic development or sufficient innate levels of hormone during late fetal development. In both instances, continued exposure to high levels of TH after birth and throughout life was needed. The hormonal dependencies correlated with severely delayed appearance of parvalbumin-immunoreactive GABAergic interneurons and increased numbers of calretinin-immunoreactive cells in the neocortex. This resulted in reduced numbers of fast spiking interneurons and defects in cortical network activity. The identification of locomotor deficiencies caused by insufficient supply of TH during fetal/perinatal development and their correlation with subtype-specific interneurons suggest a previously unknown basis for the neuronal consequences of endemic cretinism and untreated congenital hypothyroidism, and specifies TR alpha 1 as the receptor isoform mediating these effects.

  • 28.
    Wallén-Mackenzie, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Gezelius, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Thoby-Brisson, Muriel
    Nygård, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Enjin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Fujiyama, Fumino
    Fortin, Gilles
    Kullander, Klas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Vesicular glutamate transporter 2 is required for central respiratory rhythm generation but not for locomotor central pattern generation2006In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 26, no 47, p. 12294-12307Article in journal (Refereed)
    Abstract [en]

    Glutamatergic excitatory neurotransmission is dependent on glutamate release from presynaptic vesicles loaded by three members of the solute carrier family, Slc17a6-8, which function as vesicular glutamate transporters (VGLUTs). Here, we show that VGLUT2 (Slc17a6) is required for life ex utero. Vglut2 null mutant mice die immediately after birth because of the absence of respiratory behavior. Investigations at embryonic stages revealed that neural circuits in the location of the pre-Botzinger (PBC) inspiratory rhythm generator failed to become active. However, neurons with bursting pacemaker properties and anatomical integrity of the PBC area were preserved. Vesicles at asymmetric synapses were fewer and malformed in the Vglut2 null mutant hindbrain, probably causing the complete disruption of AMPA/kainate receptor-mediated synaptic activity in mutant PBC cells. The functional deficit results from an inability of PBC neurons to achieve synchronous activation. In contrast to respiratory rhythm generation, the locomotor central pattern generator of Vglut2 null mutant mice displayed normal rhythmic and coordinated activity, suggesting differences in their operating principles. Hence, the present study identifies VGLUT2-mediated signaling as an obligatory component of the developing respiratory rhythm generator.

  • 29.
    Wallén-Mackenzie, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Nordenankar, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Fejgin, Kim
    Lagerström, Malin C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Emilsson, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Wass, Caroline
    Andersson, Daniel
    Egecioglu, Emil
    Andersson, My
    Strandberg, Joakim
    Lindhe, Örjan
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Chergui, Karima
    Hanse, Eric
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Fredriksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Svensson, Lennart
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kullander, Klas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Restricted cortical and amygdaloid removal of vesicular glutamate transporter 2 in preadolescent mice impacts dopaminergic activity and neuronal circuitry of higher brain function2009In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 29, no 7, p. 2238-2251Article in journal (Refereed)
    Abstract [en]

    A major challenge in neuroscience is to resolve the connection between gene functionality, neuronal circuits, and behavior. Most, if not all, neuronal circuits of the adult brain contain a glutamatergic component, the nature of which has been difficult to assess because of the vast cellular abundance of glutamate. In this study, we wanted to determine the role of a restricted subpopulation of glutamatergic neurons within the forebrain, the Vglut2-expressing neurons, in neuronal circuitry of higher brain function. Vglut2 expression was selectively deleted in the cortex, hippocampus, and amygdala of preadolescent mice, which resulted in increased locomotor activity, altered social dominance and risk assessment, decreased sensorimotor gating, and impaired long-term spatial memory. Presynaptic VGLUT2-positive terminals were lost in the cortex, striatum, nucleus accumbens, and hippocampus, and a downstream effect on dopamine binding site availability in the striatum was evident. A connection between the induced late-onset, chronic reduction of glutamatergic neurotransmission and dopamine signaling within the circuitry was further substantiated by a partial attenuation of the deficits in sensorimotor gating by the dopamine-stabilizing antipsychotic drug aripiprazole and an increased sensitivity to amphetamine. Somewhat surprisingly, given the restricted expression of Vglut2 in regions responsible for higher brain function, our analyses show that VGLUT2-mediated neurotransmission is required for certain aspects of cognitive, emotional, and social behavior. The present study provides support for the existence of a neurocircuitry that connects changes in VGLUT2-mediated neurotransmission to alterations in the dopaminergic system with schizophrenia-like behavioral deficits as a major outcome.

  • 30. Wang, Xiaolu
    et al.
    Hu, Bin
    Zieba, Agata
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Neumann, Nicole G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Kasper-Sonnenberg, Monika
    Honsbein, Annegret
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Hultqvist, Greta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Conze, Tim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Witt, Wolfgang
    Limbach, Christoph
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Geitmann, Matthis
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Danielson, Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Kolarow, Richard
    Niemann, Gesa
    Lessmann, Volkmar
    Kilimann, Manfred W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    A protein interaction node at the neurotransmitter release site: domains of Aczonin/Piccolo, Bassoon, CAST, and rim converge on the N-terminal domain of Munc13-12009In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 29, no 40, p. 12584-12596Article in journal (Refereed)
    Abstract [en]

    Multidomain scaffolding proteins organize the molecular machinery of neurotransmitter vesicle dynamics during synaptogenesis and synaptic activity. We find that domains of five active zone proteins converge on an interaction node that centers on the N-terminal region of Munc13-1 and includes the zinc-finger domain of Rim1, the C-terminal region of Bassoon, a segment of CAST1/ELKS2, and the third coiled-coil domain (CC3) of either Aczonin/Piccolo or Bassoon. This multidomain complex may constitute a center for the physical and functional integration of the protein machinery at the active zone. An additional connection between Aczonin and Bassoon is mediated by the second coiled-coil domain of Aczonin. Recombinant Aczonin-CC3, expressed in cultured neurons as a green fluorescent protein fusion protein, is targeted to synapses and suppresses vesicle turnover, suggesting involvements in synaptic assembly as well as activity. Our findings show that Aczonin, Bassoon, CAST1, Munc13, and Rim are closely and multiply interconnected, they indicate that Aczonin-CC3 can actively participate in neurotransmitter vesicle dynamics, and they highlight the N-terminal region of Munc13-1 as a hub of protein interactions by adding three new binding partners to its mechanistic potential in the control of synaptic vesicle priming.

  • 31.
    Ziegler, Nicole
    et al.
    Goethe Univ Frankfurt, Edinger Inst, Inst Neurol, Sch Med, D-60528 Frankfurt, Germany..
    Awwad, Khader
    Goethe Univ Frankfurt, Inst Vasc Signaling, D-60596 Frankfurt, Germany..
    Fisslthaler, Beate
    Goethe Univ Frankfurt, Inst Vasc Signaling, D-60596 Frankfurt, Germany.;German Ctr Cardiovasc Res, Partner Site Rhine Main, D-60528 Frankfurt, Germany..
    Reis, Marco
    Roche Diagnost GmbH, Roche Innovat Ctr Penzberg, Oncol, Pharma Res & Early Dev, D-82377 Penzberg, Germany..
    Devraj, Kavi
    Goethe Univ Frankfurt, Edinger Inst, Inst Neurol, Sch Med, D-60528 Frankfurt, Germany..
    Corada, Monica
    FIRC Inst Mol Oncol, I-20139 Milan, Italy..
    Minardi, Simone Paolo
    FIRC Inst Mol Oncol, I-20139 Milan, Italy..
    Dejana, Elisabetta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. FIRC Inst Mol Oncol, I-20139 Milan, Italy.; Univ Milan, Dipartimento Biosci, I-20133 Milan, Italy..
    Plate, Karl H.
    Goethe Univ Frankfurt, Edinger Inst, Inst Neurol, Sch Med, D-60528 Frankfurt, Germany.;German Ctr Cardiovasc Res, Partner Site Rhine Main, D-60528 Frankfurt, Germany..
    Fleming, Ingrid
    Goethe Univ Frankfurt, Inst Vasc Signaling, D-60596 Frankfurt, Germany.;German Ctr Cardiovasc Res, Partner Site Rhine Main, D-60528 Frankfurt, Germany..
    Liebner, Stefan
    Goethe Univ Frankfurt, Edinger Inst, Inst Neurol, Sch Med, D-60528 Frankfurt, Germany.;German Ctr Cardiovasc Res, Partner Site Rhine Main, D-60528 Frankfurt, Germany..
    beta-Catenin Is Required for Endothelial Cyp1b1 Regulation Influencing Metabolic Barrier Function2016In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 36, no 34, p. 8921-8935Article in journal (Refereed)
    Abstract [en]

    The canonical Wnt/beta-catenin signaling pathway is crucial for blood-brain barrier (BBB) formation in brain endothelial cells. Although glucose transporter 1, claudin-3, and plasmalemma vesicular-associated protein have been identified as Wnt/beta-catenin targets in brain endothelial cells, further downstream targets relevant to BBB formation and function are incompletely explored. By Affymetrix expression analysis, we show that the cytochrome P450 enzyme Cyp1b1 was significantly decreased in beta-catenin-deficient mouse endothelial cells, whereas its close homolog Cyp1a1 was upregulated in an aryl hydrocarbon receptor-dependent manner, hence indicating that beta-catenin is indispensable for Cyp1b1 but not for Cyp1a1 expression. Functionally, Cyp1b1 could generate retinoic acid from retinol leading to cell-autonomous induction of the barrier-related ATP-binding cassette transporter P-glycoprotein. Cyp1b1 could also generate 20-hydroxyeicosatetraenoic acid from arachidonic acid, decreasing endothelial barrier function in vitro. In mice in vivo pharmacological inhibition of Cyp1b1 increased BBB permeability for small molecular tracers, and Cyp1b1 was downregulated in glioma vessels in which BBB function is lost. Hence, we propose Cyp1b1 as a target of beta-catenin indirectly influencing BBB properties via its metabolic activity, and as a potential target for modulating barrier function in endothelial cells.

  • 32. Örstavik, K.
    et al.
    Namer, B.
    Schmidt, Roland
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Schmelz, M.
    Hilliges, M.
    Weidner, C.
    Carr, R.W.
    Handwerker, H.
    Jorum, E.
    Torebjörk, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Abnormal function of C-fibers in patients with diabetic neuropathy2006In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 26, no 44, p. 11287-11294Article in journal (Refereed)
    Abstract [en]

    The mechanisms underlying the development of painful and nonpainful neuropathy associated with diabetes mellitus are unclear. We have obtained microneurographic recordings from unmyelinated fibers in eight patients with diabetes mellitus, five with painful neuropathy, and three with neuropathy without pain. All eight patients had large-fiber neuropathy, and seven patients had pathological thermal thresholds in their feet, indicating the involvement of small-caliber nerve fibers. A total of 163 C-fibers were recorded at knee level from the common peroneal nerve in the patients (36-67 years old), and these were compared with 77 C-fibers from healthy controls (41-64 years old). The ratio of mechano-responsive to mechano-insensitive nociceptors was similar to 2:1 in the healthy controls, whereas in the patients, it was 1:2. In patients, a fairly large percentage of characterized fibers (12.5% in nonpainful and 18.9% in painful neuropathy) resembled mechano-responsive nociceptors that had lost their mechanical and heat responsiveness. Such fibers were rarely encountered in age-matched controls (3.2%). Afferent fibers with spontaneous activity or mechanical sensitization were found in both patient groups. We conclude that small-fiber neuropathy in diabetes affects receptive properties of nociceptors that leads to an impairment of mechano-responsive nociceptors.

1 - 32 of 32
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