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γ-Aminobutyric A Receptor (GABAAR) Regulates Aquaporin 4 Expression in the Subependymal Zone

RELEVANCE TO NEURAL PRECURSORS AND WATER EXCHANGE*
  • Yuting Li
    Footnotes
    Affiliations
    From the Department of Neurobiology, Interdisciplinary Center for Neurosciences, University of Heidelberg, Im Neuenheimer Feld 364, 69120 Heidelberg and
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  • Udo Schmidt-Edelkraut
    Affiliations
    From the Department of Neurobiology, Interdisciplinary Center for Neurosciences, University of Heidelberg, Im Neuenheimer Feld 364, 69120 Heidelberg and
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  • Fabian Poetz
    Footnotes
    Affiliations
    From the Department of Neurobiology, Interdisciplinary Center for Neurosciences, University of Heidelberg, Im Neuenheimer Feld 364, 69120 Heidelberg and
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  • Ilaria Oliva
    Affiliations
    From the Department of Neurobiology, Interdisciplinary Center for Neurosciences, University of Heidelberg, Im Neuenheimer Feld 364, 69120 Heidelberg and
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  • Claudia Mandl
    Affiliations
    From the Department of Neurobiology, Interdisciplinary Center for Neurosciences, University of Heidelberg, Im Neuenheimer Feld 364, 69120 Heidelberg and
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  • Gabriele Hölzl-Wenig
    Affiliations
    From the Department of Neurobiology, Interdisciplinary Center for Neurosciences, University of Heidelberg, Im Neuenheimer Feld 364, 69120 Heidelberg and
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  • Kai Schönig
    Affiliations
    the Department of Molecular Biology, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, J5 Mannheim, Germany
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  • Dusan Bartsch
    Affiliations
    the Department of Molecular Biology, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, J5 Mannheim, Germany
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  • Francesca Ciccolini
    Correspondence
    To whom correspondence should be addressed. Tel.: 49-6221-548696; Fax: 49-6221-546700;
    Affiliations
    From the Department of Neurobiology, Interdisciplinary Center for Neurosciences, University of Heidelberg, Im Neuenheimer Feld 364, 69120 Heidelberg and
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  • Author Footnotes
    * This work was supported by a grant from the Deutsche Forschungsgemeinschaft.
    1 Present address: Helmholtz Young Investigator Group, Normal and Neoplastic CNS Stem Cells, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 581, 69120 Heidelberg, Germany.
    2 Present address: Helmholtz Young Investigator Group, Posttranscriptional Control of Gene Expression, German Cancer Research Center (DKFZ), Heidelberg, Germany, and Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), Germany.
Open AccessPublished:December 24, 2014DOI:https://doi.org/10.1074/jbc.M114.618686
      Activation of γ-aminobutyric A receptors (GABAARs) in the subependymal zone (SEZ) induces hyperpolarization and osmotic swelling in precursors, thereby promoting surface expression of the epidermal growth factor receptor (EGFR) and cell cycle entry. However, the mechanisms underlying the GABAergic modulation of cell swelling are unclear. Here, we show that GABAARs colocalize with the water channel aquaporin (AQP) 4 in prominin-1 immunopositive (P+) precursors in the postnatal SEZ, which include neural stem cells. GABAAR signaling promotes AQP4 expression by decreasing serine phosphorylation associated with the water channel. The modulation of AQP4 expression by GABAAR signaling is key to its effect on cell swelling and EGFR expression. In addition, GABAAR function also affects the ability of neural precursors to swell in response to an osmotic challenge in vitro and in vivo. Thus, the regulation of AQP4 by GABAARs is involved in controlling activation of neural stem cells and water exchange dynamics in the SEZ.

      Introduction

      In the subependymal zone (SEZ),
      The abbreviations used are: SEZ
      subependymal zone
      NSC
      neural stem cell
      AQP
      aquaporin
      EGFR
      EGF receptor
      ANOVA
      analysis of variance
      Cal-C
      calphostin C
      TAP
      transit amplifying precursor
      PLA
      proximity ligation assay
      NBA
      neurobasal
      FSC
      forward scattering
      BFA
      brefeldin-A
      qRT
      quantitative reverse transcription.
      the largest neurogenic region in the adult murine brain, neural stem cells (NSCs) give rise to neuroblasts throughout adulthood (
      • Lois C.
      • García-Verdugo J.M.
      • Alvarez-Buylla A.
      Chain migration of neuronal precursors.
      ). Adult NSCs contact the blood vessels at the basal cell side and extend a primary cilium into the lateral ventricle at the apical side (
      • Mirzadeh Z.
      • Merkle F.T.
      • Soriano-Navarro M.
      • Garcia-Verdugo J.M.
      • Alvarez-Buylla A.
      Neural stem cells confer unique pinwheel architecture to the ventricular surface in neurogenic regions of the adult brain.
      ). The polarized structure of NSCs is reflected by the expression of prominin-1 at the tip of the primary cilium (
      • Dubreuil V.
      • Marzesco A.M.
      • Corbeil D.
      • Huttner W.B.
      • Wilsch-Bräuninger M.
      Midbody and primary cilium of neural progenitors release extracellular membrane particles enriched in the stem cell marker prominin-1.
      ). Although they are largely quiescent, prominin-1 immunopositive (P+) NSCs can undergo activation and enter the cell cycle in normal conditions and upon injury (
      • Coskun V.
      • Wu H.
      • Blanchi B.
      • Tsao S.
      • Kim K.
      • Zhao J.
      • Biancotti J.C.
      • Hutnick L.
      • Krueger Jr., R.C.
      • Fan G.
      • de Vellis J.
      • Sun Y.E.
      CD133+ neural stem cells in the ependyma of mammalian postnatal forebrain.
      ). Activated NSCs and transit-amplifying precursors (TAPs) express high levels of the epidermal growth factor receptor (EGFR) at the cell surface (Ehigh), and they proliferate in vivo and in vitro in response to EGF (
      • Doetsch F.
      • Petreanu L.
      • Caille I.
      • Garcia-Verdugo J.M.
      • Alvarez-Buylla A.
      EGF converts transit-amplifying neurogenic precursors in the adult brain into multipotent stem cells.
      ). Because EGFR is progressively down-regulated during the differentiation of intermediate progenitors into neuroblasts (
      • Cesetti T.
      • Obernier K.
      • Bengtson C.P.
      • Fila T.
      • Mandl C.
      • Hölzl-Wenig G.
      • Wörner K.
      • Eckstein V.
      • Ciccolini F.
      Analysis of stem cell lineage progression in the neonatal subventricular zone identifies EGFR+/NG2 cells as transit-amplifying precursors.
      ), prominin-1 and EGFR represent useful markers for the efficient identification and isolation of activated NSCs and TAPs (
      • Carrillo-García C.
      • Suh Y.
      • Obernier K.
      • Hölzl-Wenig G.
      • Mandl C.
      • Ciccolini F.
      Multipotent precursors in the anterior and hippocampal subventricular zone display similar transcription factor signatures but their proliferation and maintenance are differentially regulated.
      ,
      • Obernier K.
      • Simeonova I.
      • Fila T.
      • Mandl C.
      • Hölzl-Wenig G.
      • Monaghan-Nichols P.
      • Ciccolini F.
      Expression of Tlx in both stem cells and transit amplifying progenitors regulates stem cell activation and differentiation in the neonatal lateral subependymal zone.
      ,
      • Khatri P.
      • Obernier K.
      • Simeonova I.K.
      • Hellwig A.
      • Hölzl-Wenig G.
      • Mandl C.
      • Scholl C.
      • Wölfl S.
      • Winkler J.
      • Gaspar J.A.
      • Sachinidis A.
      • Ciccolini F.
      Proliferation and cilia dynamics in neural stem cells prospectively isolated from the SEZ.
      ).
      In the pre- and postnatal SEZ, the inhibitory neurotransmitter γ-aminobutyric acid (GABA) through the activation of its type A receptors (GABAARs) affects multiple aspects of neurogenesis, including proliferation of the various precursor types, cell migration, and differentiation (
      • Cesetti T.
      • Ciccolini F.
      • Li Y.
      GABA not only a neurotransmitter: osmotic regulation by GABA(A)R signaling.
      ,
      • Suh H.
      • Deng W.
      • Gage F.H.
      Signaling in adult neurogenesis.
      ,
      • Vicini S.
      The role of GABA and glutamate on adult neurogenesis.
      ). In neuroblasts, GABAAR-induced cell depolarization was consistently found to decrease proliferation and migration (
      • Nguyen L.
      • Malgrange B.
      • Breuskin I.
      • Bettendorff L.
      • Moonen G.
      • Belachew S.
      • Rigo J.M.
      Autocrine/paracrine activation of the GABA(A) receptor inhibits the proliferation of neurogenic polysialylated neural cell adhesion molecule-positive (PSA-NCAM+) precursor cells from postnatal striatum.
      ,
      • Bolteus A.J.
      • Bordey A.
      GABA release and uptake regulate neuronal precursor migration in the postnatal subventricular zone.
      ). In contrast, the effect of GABAAR activation on the proliferation of NSCs and TAPs is still debated (
      • Aprea J.
      • Calegari F.
      Bioelectric state and cell cycle control of mammalian neural stem cells.
      ). The multiple effects elicited by GABAAR activation are likely a consequence of the differences in magnitude and direction of the anionic GABAergic currents. In primary precursors, they are small and hyperpolarizing leading to osmotic swelling, whereas the GABAergic currents increase in magnitude and turn depolarizing in differentiating neuroblasts (
      • Andäng M.
      • Hjerling-Leffler J.
      • Moliner A.
      • Lundgren T.K.
      • Castelo-Branco G.
      • Nanou E.
      • Pozas E.
      • Bryja V.
      • Halliez S.
      • Nishimaru H.
      • Wilbertz J.
      • Arenas E.
      • Koltzenburg M.
      • Charnay P.
      • El Manira A.
      • Ibañez C.F.
      • Ernfors P.
      Histone H2AX-dependent GABA(A) receptor regulation of stem cell proliferation.
      ,
      • Cesetti T.
      • Fila T.
      • Obernier K.
      • Bengtson C.P.
      • Li Y.
      • Mandl C.
      • Hölzl-Wenig G.
      • Ciccolini F.
      GABAA receptor signaling induces osmotic swelling and cell cycle activation of neonatal prominin+ precursors.
      ,
      • Ming G.L.
      • Song H.
      Adult neurogenesis in the mammalian brain: significant answers and significant questions.
      ).
      Aquaporins (AQPs), provide a major pathway for osmotically driven water transport through cell membranes. AQP4, the predominant isoform in the central nervous system, is extensively expressed in adult neurogenic regions such as the SEZ, especially in ependymal cells and subependymal astrocytes (
      • Venero J.L.
      • Vizuete M.L.
      • Machado A.
      • Cano J.
      Aquaporins in the central nervous system.
      ). Adult NSCs express AQP4 (
      • Cavazzin C.
      • Ferrari D.
      • Facchetti F.
      • Russignan A.
      • Vescovi A.L.
      • La Porta C.A.
      • Gritti A.
      Unique expression and localization of aquaporin-4 and aquaporin-9 in murine and human neural stem cells and in their glial progeny.
      ), and genetic ablation of AQP4 affected multiple aspects of NSC function, including proliferation (
      • Kong H.
      • Fan Y.
      • Xie J.
      • Ding J.
      • Sha L.
      • Shi X.
      • Sun X.
      • Hu G.
      AQP4 knockout impairs proliferation, migration and neuronal differentiation of adult neural stem cells.
      ). However, the molecular mechanisms underlying the effects of AQP4 on NSCs are still unclear.
      Genetic ablation of AQP4 expression leads to a marked reduction of water uptake through the blood-brain barrier (
      • Haj-Yasein N.N.
      • Vindedal G.F.
      • Eilert-Olsen M.
      • Gundersen G.A.
      • Skare Ø.
      • Laake P.
      • Klungland A.
      • Thorén A.E.
      • Burkhardt J.M.
      • Ottersen O.P.
      • Nagelhus E.A.
      Glial-conditional deletion of aquaporin-4 (Aqp4) reduces blood-brain water uptake and confers barrier function on perivascular astrocyte endfeet.
      ) and of brain swelling following cytotoxic brain edema (
      • Papadopoulos M.C.
      • Verkman A.S.
      Aquaporin-4 and brain edema.
      ,
      • Thrane A.S.
      • Rappold P.M.
      • Fujita T.
      • Torres A.
      • Bekar L.K.
      • Takano T.
      • Peng W.
      • Wang F.
      • Rangroo Thrane V.
      • Enger R.
      • Haj-Yasein N.N.
      • Skare Ø.
      • Holen T.
      • Klungland A.
      • Ottersen O.P.
      • Nedergaard M.
      • Nagelhus E.A.
      Critical role of aquaporin-4 (AQP4) in astrocytic Ca2+ signaling events elicited by cerebral edema.
      ). The expression of AQP4 is not constant but is functionally regulated at the levels of both transcription and channel assembly (
      • Vizuete M.L.
      • Venero J.L.
      • Vargas C.
      • Ilundáin A.A.
      • Echevarría M.
      • Machado A.
      • Cano J.
      Differential upregulation of aquaporin-4 mRNA expression in reactive astrocytes after brain injury: potential role in brain edema.
      ,
      • Taniguchi M.
      • Yamashita T.
      • Kumura E.
      • Tamatani M.
      • Kobayashi A.
      • Yokawa T.
      • Maruno M.
      • Kato A.
      • Ohnishi T.
      • Kohmura E.
      • Tohyama M.
      • Yoshimine T.
      Induction of aquaporin-4 water channel mRNA after focal cerebral ischemia in rat.
      ,
      • Saadoun S.
      • Papadopoulos M.C.
      • Davies D.C.
      • Krishna S.
      • Bell B.A.
      Aquaporin-4 expression is increased in oedematous human brain tumours.
      ). Phosphorylation of AQP4 has been consistently reported as a mechanism underlying the regulation of channel assembly as well as water permeability (
      • Zelenina M.
      • Zelenin S.
      • Bondar A.A.
      • Brismar H.
      • Aperia A.
      Water permeability of aquaporin-4 is decreased by protein kinase C and dopamine.
      ,
      • Carmosino M.
      • Procino G.
      • Tamma G.
      • Mannucci R.
      • Svelto M.
      • Valenti G.
      Trafficking and phosphorylation dynamics of AQP4 in histamine-treated human gastric cells.
      ). Nevertheless, little is known concerning the regulation of AQP4 expression in the SEZ lineage and the relationship between osmolarity and neurogenesis.
      In this study, we provide evidence that within the SEZ GABAAR signaling modulates the expression of AQP4 at the cell surface. We show that the GABAergic-dependent osmotic regulation in this region affects EGFR expression in neural precursors and water uptake upon osmotic challenge.

      DISCUSSION

      We have previously shown that GABAAR activation leads to hyperpolarization and osmotic swelling in SEZ stem cells causing expression of EGFR at the cell surface (
      • Cesetti T.
      • Fila T.
      • Obernier K.
      • Bengtson C.P.
      • Li Y.
      • Mandl C.
      • Hölzl-Wenig G.
      • Ciccolini F.
      GABAA receptor signaling induces osmotic swelling and cell cycle activation of neonatal prominin+ precursors.
      ). In this study, we provide evidence that in addition to Cl influx activation of GABAAR in SEZ precursors also modulates the surface expression of AQP4. We found that the effect of GABAAR activation on osmotic tension not only affected EGFR expression in the SEZ but also water retention. As the primary function of AQP4 concerns the regulation of water exchange through the various compartments of the brain (
      • Benfenati V.
      • Ferroni S.
      Water transport between CNS compartments: functional and molecular interactions between aquaporins and ion channels.
      ), it is very likely that the effect of bicuculline on water retention is a consequence of its modulation of AQP4 expression.
      Within the SEZ, the AQP4 channel is expressed in the ependymal layer, where it contributes to maintain its integrity, and in the underlying germinal epithelium in precursors and to a lesser extent in niche astrocytes (
      • Cavazzin C.
      • Ferrari D.
      • Facchetti F.
      • Russignan A.
      • Vescovi A.L.
      • La Porta C.A.
      • Gritti A.
      Unique expression and localization of aquaporin-4 and aquaporin-9 in murine and human neural stem cells and in their glial progeny.
      ). Consistent with this, we found that in neonatal mice the expression of AQP4 is mainly confined to the populations of P+/Elow and P+/Ehigh cells, which at this age include most of the ependymal cells as well as NSCs (
      • Khatri P.
      • Obernier K.
      • Simeonova I.K.
      • Hellwig A.
      • Hölzl-Wenig G.
      • Mandl C.
      • Scholl C.
      • Wölfl S.
      • Winkler J.
      • Gaspar J.A.
      • Sachinidis A.
      • Ciccolini F.
      Proliferation and cilia dynamics in neural stem cells prospectively isolated from the SEZ.
      ). The latter are particularly enriched within in the P+/Ehigh population representing activated NSCs (
      • Carrillo-García C.
      • Suh Y.
      • Obernier K.
      • Hölzl-Wenig G.
      • Mandl C.
      • Ciccolini F.
      Multipotent precursors in the anterior and hippocampal subventricular zone display similar transcription factor signatures but their proliferation and maintenance are differentially regulated.
      ,
      • Obernier K.
      • Simeonova I.
      • Fila T.
      • Mandl C.
      • Hölzl-Wenig G.
      • Monaghan-Nichols P.
      • Ciccolini F.
      Expression of Tlx in both stem cells and transit amplifying progenitors regulates stem cell activation and differentiation in the neonatal lateral subependymal zone.
      ,
      • Khatri P.
      • Obernier K.
      • Simeonova I.K.
      • Hellwig A.
      • Hölzl-Wenig G.
      • Mandl C.
      • Scholl C.
      • Wölfl S.
      • Winkler J.
      • Gaspar J.A.
      • Sachinidis A.
      • Ciccolini F.
      Proliferation and cilia dynamics in neural stem cells prospectively isolated from the SEZ.
      ). In contrast, prospectively isolated neonatal P/Ehigh TAPs and P/Elow neuroblasts expressed very low levels of AQP4 mRNA, showing that the AQP4 is rapidly down-regulated during neuronal differentiation. However, at the protein level the differences between P+ and P cells were reduced, suggesting a relative stability of the water channel. Moreover, in culture conditions the AQP4 immunoreactivity was observed in most of the cells, which likely reflects the selection for precursor cells in culture conditions.
      In the SEZ, functional GABAAR currents have been recorded from both precursors and more mature neuronal progenitors, although their size and directions differ in the two cell groups (
      • Cesetti T.
      • Fila T.
      • Obernier K.
      • Bengtson C.P.
      • Li Y.
      • Mandl C.
      • Hölzl-Wenig G.
      • Ciccolini F.
      GABAA receptor signaling induces osmotic swelling and cell cycle activation of neonatal prominin+ precursors.
      ). In immature neural precursors, GABAAR currents are hyperpolarizing and relatively small, which may lead to a requirement for proximity within the cell between the anionic channel and the targeted proteins. Indeed, our data indicate that GABAARs and AQP4 localize closely. Previous analyses have shown that the localization of AQP4 at the end-feet of perivascular astrocytes is dependent on its interaction with syntrophin within the dystrophin-glycoprotein complex (
      • Bragg A.D.
      • Amiry-Moghaddam M.
      • Ottersen O.P.
      • Adams M.E.
      • Froehner S.C.
      Assembly of a perivascular astrocyte protein scaffold at the mammalian blood-brain barrier is dependent on α-syntrophin.
      ,
      • Binder D.K.
      • Nagelhus E.A.
      • Ottersen O.P.
      Aquaporin-4 and epilepsy.
      ). Because the dystrophin complex also plays a role in the assembly of the GABAARs, it is possible that both channels interact with the dystrophin complex. However, this possibility may only concern the subset of SEZ astrocytes, including P+ NSCs. In fact, although globules containing dystroglycan and other dystrophin-glycoprotein complex components have been observed in ependymal cells, the interaction between dystrophin-glycoprotein complex and AQP4 appears not essential for the localization of AQP4 within this cell group (
      • Nicchia G.P.
      • Rossi A.
      • Nudel U.
      • Svelto M.
      • Frigeri A.
      Dystrophin-dependent and -independent AQP4 pools are expressed in the mouse brain.
      ).
      Multiple kinases and phosphorylation sites have been involved in the regulation of the phosphorylation status of AQP4 (
      • Zelenina M.
      • Zelenin S.
      • Bondar A.A.
      • Brismar H.
      • Aperia A.
      Water permeability of aquaporin-4 is decreased by protein kinase C and dopamine.
      ,
      • Carmosino M.
      • Procino G.
      • Tamma G.
      • Mannucci R.
      • Svelto M.
      • Valenti G.
      Trafficking and phosphorylation dynamics of AQP4 in histamine-treated human gastric cells.
      ). For example, at the invasive hedges of gliomas, PKC is closely localized to clusters of AQP4 and Cl channels and transporters. In this system, PKC activation inhibits tumor cell migration and invasiveness by promoting AQP4 phosphorylation on serine 180 (
      • McCoy E.S.
      • Haas B.R.
      • Sontheimer H.
      Water permeability through aquaporin-4 is regulated by protein kinase C and becomes rate-limiting for glioma invasion.
      ). Instead, in kidney epithelial cells phosphorylation of serine 279 by casein kinase II leads to lysosomal targeting and degradation of the water channel (
      • Johnstone S.R.
      • Kroncke B.M.
      • Straub A.C.
      • Best A.K.
      • Dunn C.A.
      • Mitchell L.A.
      • Peskova Y.
      • Nakamoto R.K.
      • Koval M.
      • Lo C.W.
      • Lampe P.D.
      • Columbus L.
      • Isakson B.E.
      MAPK phosphorylation of connexin 43 promotes binding of cyclin E and smooth muscle cell proliferation.
      ). In contrast, we found here that GABAAR activation decreased phospho-AQP4 and enhanced the expression of the water channel at the cell surface, which was prevented by BFA. This suggests that the GABAergic regulation of phospho-AQP4 modulates the anterograde transport of AQP4. Thus, the mechanisms underlying the regulation of the water channel are complex and may be dependent on the cellular context.
      In contrast to AQP4, our data indicate that GABAARs regulate surface EGFR expression mainly by affecting osmotic tension, as endogenous GABAAR signaling maintains EGFR expression only within P+ cells that express high levels of the water channel. Moreover, blockade of GABAARs did not affect EGFR expression in precursors isolated from AQP4 KO mice, and EGFR expression was similarly enhanced by forced activation of GABAARs and hypo-osmotic treatment. However, the exposure to hypo-osmotic conditions affected EGFR expression also in AQP4 cells. It is unlikely that these AQP4 cells represent either neuroblasts or SEZ astrocytes, as they do not express EGFR. Rather they may represent cells in the process of down-regulating EGFR before differentiating into neuroblasts. This is consistent with our previous findings showing that the amount of EGFR transcripts and protein peaks within the population of Ehigh cells and that EGFR expression is rapidly down-regulated during the transition from pre-neuroblasts to neuroblasts (
      • Cesetti T.
      • Obernier K.
      • Bengtson C.P.
      • Fila T.
      • Mandl C.
      • Hölzl-Wenig G.
      • Wörner K.
      • Eckstein V.
      • Ciccolini F.
      Analysis of stem cell lineage progression in the neonatal subventricular zone identifies EGFR+/NG2 cells as transit-amplifying precursors.
      ). Thus, our findings unveil a new mechanism by which GABAARs regulate osmotic tension in the SEZ precursors, thereby modulating EGFR expression and water exchange in this region.

      Acknowledgments

      The AQP4 KO mice were generously provided by Dr. Erlend A. Nagelhus, Institute of Basic Medical Sciences, University of Oslo, Norway.

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