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  • 1.
    Aldskogius, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. neuroanatomi.
    Repairing CNS myelin: astrocytes have to do their jobs2005In: Experimental Neurology, ISSN 0014-4886, E-ISSN 1090-2430, Vol. 192, no 1, p. 7-10Article in journal (Refereed)
  • 2. Berg, Alexander
    et al.
    Zelano, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Stephan, Alexander
    Thams, Sebastian
    Barres, Ben A.
    Pekny, Milos
    Pekna, Marcela
    Cullheim, Staffan
    Reduced removal of synaptic terminals from axotomized spinal motoneurons in the absence of complement C32012In: Experimental Neurology, ISSN 0014-4886, E-ISSN 1090-2430, Vol. 237, no 1, p. 8-17Article in journal (Refereed)
    Abstract [en]

    Complement proteins C1q and C3 play a critical role in synaptic elimination during development. Axotomy of spinal motoneurons triggers removal of synaptic terminals from the cell surface of motoneurons by largely unknown mechanisms. We therefore hypothesized that the complement system is involved also in synaptic stripping of injured motoneurons. In the sciatic motor pool of wild type (WT) mice, the immunoreactivity (IR) for both C1q and C3 was increased after sciatic nerve transection (SNT). Mice deficient in C3 (C3(-/-)) showed a reduced loss of synaptic terminals from injured motoneurons at one week after SNT, as assessed by immunoreactivity for synaptic markers and electron microscopy. In particular, the removal of putative inhibitory terminals, immunopositive for vesicular inhibitory amino acid transporter (VIAAT) and ultrastructurally identified as type F synapses, was reduced in C3(-/-) mice. In contrast, lesion-induced removal of nerve terminals in C1q(-/-) mice appeared similar to WT mice. Growth associated protein (GAP)-43 mRNA expression in lesioned motoneurons increased much more in C3(-/-) compared to WT mice after SNT. After sciatic nerve crush (SNC), the C3(-/-) mice showed a faster functional recovery, assessed as grip strength, compared to WT mice. No differences were detected regarding nerve inflammation at the site of injury or pattern of muscle reinnervation. These data indicate that a non-classical pathway of complement activation is involved in axotomy-induced adult synapse removal, and that its inhibition promotes functional recovery.

  • 3.
    Ekegren, Titti
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Askmark, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Aquilonius, Sten-Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Gomes-Trolin, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Methionine adenosyltransferase activity in erythrocytes and spinal cord of patients with sporadic amyotrophic lateral sclerosis1999In: Experimental Neurology, ISSN 0014-4886, E-ISSN 1090-2430, Vol. 158, no 2, p. 422-427Article in journal (Refereed)
    Abstract [en]

    The role of transmethylation mechanisms in the etiology of amyotrophic lateral sclerosis (ALS) is hitherto unexplored. The activity of L-methionine S-adenosyltransferase (MAT), a regulatory enzyme of S-adenosylmethionine biosynthesis, was investigated in erythrocytes of 21 patients with ALS, spinal cord specimens of 7 ALS patients, and matched controls. In ALS patients the activity of MAT in erythrocytes was sex-dependent. In comparison with controls, the male group presented a 33% higher Vmax (PF0.05) and a 41% decrease in the affinity of MAT for methionine (Km, PF0.05). The type of ALS onset (limb or bulbar), age, or duration of the disease did not influence erythrocyte MAT activity. In the spinal cord, the activity of MAT was homogeneously distributed through dorsal horn, ventral horn, and white matter. Comparisons between data from controls and ALS patients and analysis of sex effect showed no significant differences. The kinetic difference of erythrocyte MAT in the male group of ALS patients might be interesting to explore since it is well known that there is a male predominance of 1.5 to 2.5:1 inALS.

  • 4.
    Erlandsson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Lin, Chia-Hsun Anthony
    Yu, Fenggang
    Morshead, Cindi M.
    Immunosuppression promotes endogenous neural stem and progenitor cell migration and tissue regeneration after ischemic injury2011In: Experimental Neurology, ISSN 0014-4886, E-ISSN 1090-2430, Vol. 230, no 1, p. 48-57Article in journal (Refereed)
    Abstract [en]

    Recent work has demonstrated that self-repair in the adult brain can be augmented by the infusion of growth factors to activate endogenous neural precursor cells that contribute to new tissue formation and functional recovery in a model of stroke. Using both a genetic model and drug treatment, we demonstrate that immunosuppression mimics the effects of growth factor activation, including tissue regeneration, neural precursor cell migration and functional recovery following ischemic injury. In the absence of growth factor treatment, mice with a functional immune system develop a prominent cavity in the cortex underlying the ischemic injury. In untreated immunodeficient NOD/SCID mice, however, the cortical cavity forms but is then filled with regenerated cortical tissue containing glial cells and subependyma derived neural stem and progenitor cells that migrate from their niche lining the lateral ventricles. The daily administration of Cyclosporine A also results in endogenous neural precursor cell migration and regenerated cortical tissue at the site of the cortical injury. Different from growth factor-treated animals is the finding that the regenerated cortical tissue in immunosuppressed animals is devoid of new neurons. Interestingly, both the growth factor and immunosuppressed (NOD/SCID and Cyclosporine A) treated animals displayed functional behavioural recovery despite the lack of neurogenesis within the regenerated cortical tissue. This article is part of a Special Issue entitled "Interaction between repair, disease, & inflammation."

  • 5. Friedman, W J
    et al.
    Ibáñez, C F
    Hallböök, F
    Persson, H
    Cain, L D
    Dreyfus, C F
    Black, I B
    Differential actions of neurotrophins in the locus coeruleus and basal forebrain.1993In: Experimental Neurology, ISSN 0014-4886, E-ISSN 1090-2430, Vol. 119, no 1, p. 72-8Article in journal (Refereed)
    Abstract [en]

    The neurotrophin gene family, including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and NT-4/NT-5, supports the survival of distinct peripheral neurons, however, actions upon central neurons are relatively undefined. In this study we have compared different neurotrophins in the regulation of neuronal survival and function using dissociated embryonic cell cultures from two brain regions, the basal forebrain (BF) and locus coeruleus (LC). In the BF, NGF increased choline acetyl transferase (ChAT) activity, but did not influence cholinergic cell survival. In contrast to NGF, BDNF, NT-3, and the novel neurotrophin, NT-4, all increased ChAT activity and cholinergic cell survival. We also examined embryonic LC neurons in culture. LC neurons are unresponsive to NGF. In contrast, NT-3 and NT-4 elicited significant increases in survival of noradrenergic LC neurons, the first demonstration of trophic effects in this critical brain region. Identification of factors supporting coeruleal and basal forebrain neuronal survival may provide insight into mechanisms mediating degeneration of these disparate structures in clinical disorders.

  • 6. Iderberg, Hanna
    et al.
    Rylander, Daniella
    Bimpisidis, Zisis
    Cenci, Maria Angela
    Modulating mGluR5 and 5-HT1A/1B receptors to treat  L-DOPA-induced dyskinesia: Effects of combined treatment and possible mechanisms of action2013In: Experimental Neurology, ISSN 0014-4886, E-ISSN 1090-2430, Vol. 250, p. 116-124Article in journal (Refereed)
  • 7.
    Kalliomäki, Maija
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Kieseritzky, Johanna V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hand Surgery.
    Schmidt, Roland
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Hägglöf, Björn
    Karlsten, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Sjögren, Niclas
    Albrecht, Phil
    Gee, Lucy
    Rice, Frank
    Wiig, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hand Surgery.
    Schmelz, Martin
    Gordh, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Structural and functional differences between neuropathy with and without pain?2011In: Experimental Neurology, ISSN 0014-4886, E-ISSN 1090-2430, Vol. 231, no 2, p. 199-206Article in journal (Refereed)
    Abstract [en]

    We aimed to find functional and structural differences in neuropathy between patients with and without chronic pain following nerve injury. We included 30 patients requiring hand surgery after a trauma, with 21 reporting chronic pain for more than one year after the injury, while 9 did not suffer from injury-related chronic pain. We assessed mechanical sensitivity, thermal thresholds, electrically induced pain and axon reflex erythema and cutaneous nerve fiber density in skin biopsies of the injured site and its contralateral control. Epidermal fiber density of the injured site was reduced similarly in both patient groups. Thresholds for cold and heat pain and axon reflex areas were reduced in the injured site, but did not differ between the patient groups. Only warmth thresholds were better preserved in the pain patients (35.2 vs. 38.4 degrees C). Neuronal CGRP staining did not reveal any difference between pain and non-pain patients. Epidermal innervation density correlated best to warmth detection thresholds and deeper dermal innervation density to the area of the axon reflex erythema. No specific pattern of subjective, functional or structural parameters was detected that would separate the neuropathy patients into pain and non-pain patients. Specific staining of additional targets may help to improve our mechanistic understanding of pain development.

  • 8.
    Liu, Li
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Svensson, Mikael
    Aldskogius, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Clusterin upregulation following rubrospinal tract lesion in the adult rat1999In: Experimental Neurology, ISSN 0014-4886, E-ISSN 1090-2430, Vol. 157, no 1, p. 69-76Article in journal (Refereed)
    Abstract [en]

    We have examined the expression of the multifunctional protein clusterin in the axotomized red nucleus, at the lesion site in the lateral funiculus of C3, as well as along the Wallerian degeneration in the lateral funiculus of T1. There was a marked increase in clusterin-immunoreactivity (IR) and clusterin mRNA in red nucleus nerve cell bodies. An early, transient occurrence of large, heavily clusterin-IR globules were found in axons in the spinal cord at the lesion site in C3 as well as a marked upregulation of mRNA for clusterin, presumably associated with reactive astrocytes and oligodendrocytes from 1 to 4 weeks postoperatively. Clusterin-IR and its mRNA were markedly increased in the zone of Wallerian degeneration at T1, where some strongly expressing cells were identified as oligodendrocytes. Taken together with previous changes in clusterin expression following peripheral nerve and dorsal root injury, we suggest that this protein is involved in regenerative as well as degenerative neural responses.

  • 9. Petersén, Åsa
    et al.
    Mani, Kevin
    Brundin, Patrik
    Recent advances on the pathogenesis of Huntington's disease1999In: Experimental Neurology, ISSN 0014-4886, E-ISSN 1090-2430, Vol. 157, no 1, p. 1-18Article in journal (Refereed)
    Abstract [en]

    We review recent advances regarding the pathogenesis of Huntington's disease (HD). This genetic neurodegenerative disorder is caused by an expanded CAG repeat in a gene coding for a protein, with unknown function, called huntingtin. There is selective death of striatal and cortical neurons. Both in patients and a transgenic mouse model of the disease, neuronal intranuclear inclusions, immunoreactive for huntingtin and ubiquitin, develop. Huntingtin interacts with the proteins GAPDH, HAP-1, HIP1, HIP2, and calmodulin, and a mutant huntingtin is specifically cleaved by the proapoptotic enzyme caspase 3. The pathogenetic mechanism is not known, but it is presumed that there is a toxic gain of function of the mutant huntingtin. Circumstantial evidence suggests that excitotoxicity, oxidative stress, impaired energy metabolism, and apoptosis play a role.

  • 10. Phillips, W D
    et al.
    Christadoss, P
    Losen, M
    Punga, Anna Rostedt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Shigemoto, K
    Verschuuren, J
    Vincent, A
    Guidelines for pre-clinical animal and cellular models of MuSK-myasthenia gravis2015In: Experimental Neurology, ISSN 0014-4886, E-ISSN 1090-2430, Vol. 270, no SI, p. 29-40Article in journal (Refereed)
    Abstract [en]

    Muscle-specific tyrosine kinase (MuSK) autoantibodies are the hallmark of a form of myasthenia gravis (MG) that can challenge the neurologist and the experimentalist. The clinical disease can be difficult to treat effectively. MuSK autoantibodies affect the neuromuscular junction in several ways. When added to muscle cells in culture, MuSK antibodies disperse acetylcholine receptor clusters. Experimental animals actively immunized with MuSK develop MuSK autoantibodies and muscle weakness. Weakness is associated with reduced postsynaptic acetylcholine receptor numbers, reduced amplitudes of miniature endplate potentials and endplate potentials, and failure of neuromuscular transmission. Similar impairments have been found in mice injected with IgG from MG patients positive for MuSK autoantibody (MuSK-MG). The active and passive models have begun to reveal the mechanisms by which MuSK antibodies disrupt synaptic function at the neuromuscular junction, and should be valuable in developing therapies for MuSK-MG. However, translation into new and improved treatments for patients requires procedures that are not too cumbersome but suitable for examining different aspects of MuSK function and the effects of potential therapies. Study design, conduct and analysis should be carefully considered and transparently reported. Here we review what has been learnt from animal and culture models of MuSK-MG, and offer guidelines for experimental design and conduct of studies, including sample size determination, randomization, outcome parameters and precautions for objective data analysis. These principles may also be relevant to the increasing number of other antibody-mediated diseases that are now recognized.

  • 11.
    Rostedt Punga, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Kaminski, Henry J
    Richman, David P
    Benatar, Michael
    How clinical trials of myasthenia gravis can inform pre-clinical drug development2015In: Experimental Neurology, ISSN 0014-4886, E-ISSN 1090-2430, Vol. 270, no SI, p. 78-81Article in journal (Refereed)
    Abstract [en]

    Pre-clinical evaluations often provide the rationale for therapeutic assessments in humans; however, in many diseases an agent found successful in animal models does not show efficacy in human subjects. Our contention is that the approach of rigorous, clinical trials can be used to inform how preclinical assessments should be performed. Clinical trials in humans are carefully designed investigations executed with consideration of critical methodological issues, such as pre-specified entrance criteria and validated, outcome measures coupled with power analysis to identify sample size. Blinding of evaluators of subjective measures and randomization of subjects are also critical aspects of trial performance. Investigative agents are also tested in subjects with active disease, rather than prior to disease induction as in some pre-clinical assessments. Application of standard procedures, including uniform reporting standards, would likely assist in reproducibility of pre-clinical experiments. Adapting methods of clinical trial performance will likely improve the success rate of therapeutics to ultimately achieve human use.

  • 12.
    Rostedt Punga, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Lin, Shuo
    Oliveri, Filippo
    Meinen, Sarina
    Rüeegg, Markus A.
    Muscle-selective synaptic disassembly and reorganization in MuSK antibody positive MG mice2011In: Experimental Neurology, ISSN 0014-4886, E-ISSN 1090-2430, Vol. 230, no 2, p. 207-217Article in journal (Refereed)
    Abstract [en]

    MuSK antibody seropositive (MuSK+) Myasthenia Gravis (MG) patients present a distinct selective fatigue, and sometimes atrophy, of bulbar, facial and neck muscles. Here, we study the mechanism underlying the focal muscle involvement in mice with MuSK+ experimental autoimmune MG (EAMG). 8 week-old female wildtype C57BL6 mice and transgenic mice, which express yellow fluorescence protein (YFP) in their motor neurons, were immunized with the extracellular domain of rat MuSK and compared with control mice. The soleus, EDL, sternomastoid, omohyoid, thoracic paraspinal and masseter muscles were examined for pre- and postsynaptic changes with whole mount immunostaining and confocal microscopy. Neuromuscular junction derangement was quantified and compared between muscles and correlated with transcript levels of MuSK and other postsynaptic genes. Correlating with the EAMG disease grade, the postsynaptic acetylcholine receptor (AChR) clusters were severely fragmented with a subsequent reduction also of the presynaptic nerve terminal area. Among the muscles analyzed, the thoracic paraspinal, sternomastoid and masseter muscles were more affected than the leg muscles. The masseter muscle was the most affected, leading to denervation and atrophy and this severity correlated with the lowest levels of MuSK mRNA. On the contrary, the soleus with high MuSK mRNA levels had less postsynaptic perturbation and more terminal nerve sprouting. We propose that low muscle-intrinsic MuSK levels render some muscles, such as the masseter, more vulnerable to the postsynaptic perturbation of MuSK antibodies with subsequent denervation and atrophy. These findings augment our understanding of the sometimes severe, facio-bulbar phenotype of MuSK+ MG.

  • 13.
    Silveira Broggini, Ana Clara
    et al.
    Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Neurosci & Behav, Ave Bandeirantes 3900, BR-14049900 Ribeirao Preto, SP, Brazil..
    Esteves, Ingrid Miranda
    Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Neurosci & Behav, Ave Bandeirantes 3900, BR-14049900 Ribeirao Preto, SP, Brazil..
    Romcy-Pereira, Rodrigo Neves
    Univ Fed Rio Grande do Norte, Inst Brain, Ave Nascimento de Castro 2155, BR-59056450 Natal, RN, Brazil..
    Leite, Joao Pereira
    Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Neurosci & Behav, Ave Bandeirantes 3900, BR-14049900 Ribeirao Preto, SP, Brazil..
    Leao, Richardson Naves
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics. Univ Fed Rio Grande do Norte, Inst Brain, Ave Nascimento de Castro 2155, BR-59056450 Natal, RN, Brazil..
    Pre-ictal increase in theta synchrony between the hippocampus and prefrontal cortex in a rat model of temporal lobe epilepsy2016In: Experimental Neurology, ISSN 0014-4886, E-ISSN 1090-2430, Vol. 279, p. 232-242Article in journal (Refereed)
    Abstract [en]

    The pathologically synchronized neuronal activity in temporal lobe epilepsy (TLE) can be triggered by network events that were once normal. Under normal conditions, hippocampus and medial prefrontal cortex (mPFC) work in synchrony during a variety of cognitive states. Abnormal changes in this circuit may aid to seizure onset and also help to explain the high association of TLE with mood disorders. We used a TLE rat model generated by perforant path (PP) stimulation to understand whether synchrony between dorsal hippocampal and mPFC networks is altered shortly before a seizure episode. We recorded hippocampal and mPFC local field potentials (LFPs) of animals with spontaneous recurrent seizures (SRSs) to verify the connectivity between these regions. We showed that SRSs decrease hippocampal theta oscillations whereas coherence in theta increases over time prior to seizure onset. This increase in synchrony is accompanied by a stronger coupling between hippocampal theta and mPFC gamma oscillation. Finally, using Granger causality we showed that hippocampus/mPFC synchrony increases in the pre-ictal phase and this increase is likely to be caused by hippocampal networks. The dorsal hippocampus is not directly connected to the mPFC; however, the functional coupling in theta between these two structures rises pre-ictally. Our data indicates that the increase in synchrony between dorsal hippocampus and mPFC may be predictive of seizures and may help to elucidate the network mechanisms that lead to seizure generation.

  • 14.
    Swartling, Fredrik J.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Bolin, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Phillips, Joanna J
    Dept. of Pathology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco.
    Persson, Anders I.
    Department of Neurology, Sandler Neurosciences Center, University of California, San Francisco.
    Signals that regulate the oncogenic fate of neural stem cells and progenitors2014In: Experimental Neurology, ISSN 0014-4886, E-ISSN 1090-2430, Vol. 260, p. 56-68Article, review/survey (Refereed)
    Abstract [en]

    Brain tumors have frequently been associated with a neural stem cell (NSC) origin and contain stem-like tumor cells, so-called brain tumor stem cells (BTSCs) that share many features with normal NSCs. A stem cell state of BTSCs confers resistance to radiotherapy and treatment with alkylating agents. It is also a hallmark of aggressive brain tumors and is maintained by transcriptional networks that are also active in embryonic stem cells. Advances in reprogramming of somatic cells into induced pluripotent stem (iPS) cells have further identified genes that drive stemness. In this review, we will highlight the possible drivers of stemness in medulloblastoma and glioma, the most frequent types of primary malignant brain cancer in children and adults, respectively. Signals that drive expansion of developmentally defined neural precursor cells are also active in corresponding brain tumors. Transcriptomal subgroups of human medulloblastoma and glioma match features of NSCs but also more restricted progenitors. Lessons from genetically-engineered mouse (GEM) models show that temporally and regionally defined NSCs can give rise to distinct subgroups of medulloblastoma and glioma. We will further discuss how acquisition of stem cell features may drive brain tumorigenesis from a non-NSC origin. Genetic alterations, signaling pathways, and therapy-induced changes in the tumor microenvironment can drive reprogramming networks and induce stemness in brain tumors. Finally, we propose a model where dysregulation of microRNAs (miRNAs) that normally provide barriers against reprogramming plays an integral role in promoting stemness in brain tumors.

  • 15.
    Zelano, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Mikulovic, Sanja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Patra, Kalicharan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Kühnemund, Malte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Larhammar, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Emilsson, Lina
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
    Leao, Richardson
    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.
    The synaptic protein encoded by the gene Slc10A4 suppresses epileptiform activity and regulates sensitivity to cholinergic chemoconvulsants2013In: Experimental Neurology, ISSN 0014-4886, E-ISSN 1090-2430, Vol. 239, p. 73-81Article in journal (Refereed)
    Abstract [en]

    The expanding number of disease-causing dysfunctions of synaptic proteins illustrates the importance of investigating newly discovered proteins involved in neuronal transmission. The gene Slc10A4 encodes a recently described carrier protein present in pre-synaptic terminals of cholinergic and monoaminergic neurons. The biological significance of this recently described transporter protein is currently unknown. We here investigated whether absence of the Slc10a4 protein has any impact on function of the cholinergic system. We first investigated the sensitivity of Slc10a4 null mice to cholinergic stimulus in vitro. In contrast to wild type mice, gamma oscillations occurred spontaneously in hippocampal slices from Slc10a4 null mice. Furthermore, moderate treatment of Slc10a4 null slices with the cholinergic agonist carbachol induced epileptiform activity. In vivo, 3-channel EEG measurements in freely behaving mice revealed that Slc10a4 null mice had frequent epileptiform spike-activity before treatment, and developed epileptic seizures, detected by EEG and accompanied by observable behavioral components, more rapidly after injection of the cholinergic agonist pilocarpine. Similar results were obtained on non-operated mice, as evaluated by behavioral seizures and post mortem c-Fos immunohistochemistry. Importantly, Slc10a4 null mice and wild type control mice were equally sensitive to the glutamatergic chemoconvulsant kainic acid, demonstrating that absence of Slc10a4 led to a selective cholinergic hypersensitivity. In summary, we report that absence of the recently discovered synaptic vesicle protein Slc10a4 results in increased sensitivity to cholinergic stimulation.

  • 16. Zelano, Johan
    et al.
    Wallquist, Wilhelm
    Hailer, Nils P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Cullheim, Staffan
    Expression of nectin-1, nectin-3, N-cadherin, and NCAM in spinal motoneurons after sciatic nerve transection2006In: Experimental Neurology, ISSN 0014-4886, E-ISSN 1090-2430, Vol. 201, no 2, p. 461-469Article in journal (Refereed)
    Abstract [en]

    We here study the expression patterns of the cell adhesion molecules nectin-1, nectin-3, N-cadherin, and neural cell adhesion molecule (NCAM) in motoneurons after sciatic nerve transection (SNT). Nectins are a newly discovered family of adhesion molecules that colocalize with N-cadherin in synapses and are expressed in axons during development. By in situ hybridization (ISH), we found nectin-3, N-cadherin, and NCAM mRNA in uninjured motoneurons. In uninjured animals, nectin-3 mRNA was present in a few vesicular acetylcholine transporter (VAChT)-positive cells of small motoneuron size in lamina IX of the spinal cord. SNT induced a significant increase of nectin-1, nectin-3, and NCAM mRNA, but the signal for N-cadherin mRNA was not affected. After SNT, signal for nectin-3 mRNA appeared over most motoneurons. We next investigated the presence of N-cadherin and nectin protein in synapses on spinal motoneurons by immunohistochemistry. Only N-cadherin immunoreactivity was seen in close relation to synaptophysin staining, while nectin-1 and nectin-3 immunoreactivity did not display such proximity. SNT resulted in decreased immunoreactivity for N-cadherin around the motoneuron soma, while nectin-1 and nectin-3 immunoreactivity remained unchanged. In the peripheral sciatic nerve, nectin-3 immunoreactivity was observed both in controls and following injury and nectin-3 colocalized with both neurofilament and the Schwann cell marker S100. In addition, an increased ISH signal for nectin-3 mRNA could be seen over the proximal stump of the sciatic nerve after SNT. We conclude that motoneuron injury induces complex changes in the spatiotemporal expression pattern of the investigated cell adhesion molecules.

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