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  • 1. Couchman, Kiri
    et al.
    Garrett, Andrew
    Deardorff, Adam S
    Rattay, Frank
    Resatz, Susanne
    Fyffe, Robert
    Walmsley, Bruce
    Leão, Richardson N
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Lateral superior olive function in congenital deafness2011In: Hearing Research, ISSN 0378-5955, E-ISSN 1878-5891, Vol. 277, no 1-2, p. 163-175Article in journal (Refereed)
    Abstract [en]

    The development of cochlear implants for the treatment of patients with profound hearing loss has advanced considerably in the last few decades, particularly in the field of speech comprehension. However, attempts to provide not only sound decoding but also spatial hearing are limited by our understanding of circuit adaptations in the absence of auditory input. Here we investigate the lateral superior olive (LSO), a nucleus involved in interaural level difference (ILD) processing in the auditory brainstem using a mouse model of congenital deafness (the dn/dn mouse). An electrophysiological investigation of principal neurons of the LSO from the dn/dn mouse reveals a higher than normal proportion of single spiking (SS) neurons, and an increase in the hyperpolarisation-activated I(h) current. However, inhibitory glycinergic input to the LSO appears to develop normally both pre and postsynaptically in dn/dn mice despite the absence of auditory nerve activity. In combination with previous electrophysiological findings from the dn/dn mouse, we also compile a simple Hodgkin and Huxley circuit model in order to investigate possible computational deficits in ILD processing resulting from congenital hearing loss. We find that the predominance of SS neurons in the dn/dn LSO may compensate for upstream modifications and help to maintain a functioning ILD circuit in the dn/dn mouse. This could have clinical repercussions on the development of stimulation paradigms for spatial hearing with cochlear implants.

  • 2.
    de Oliveira, Ramatis B.
    et al.
    Univ Newcastle, Sch Biomed Sci & Pharm, Callaghan, NSW, Australia;Hunter Med Res Inst, Callaghan, NSW, Australia;Univ Taquari Valley Univates, Sch Med, Hlth & Med Res Grp, Lajeado, RS, Brazil;Bairro Univ, Avelino Tallini St 171, BR-95914014 Lajeado, RS, Brazil.
    Petiz, Lyvia L.
    Univ Newcastle, Sch Biomed Sci & Pharm, Callaghan, NSW, Australia;Hunter Med Res Inst, Callaghan, NSW, Australia;Univ Fed Rio Grande do Norte, Brain Inst, Natal, RN, Brazil.
    Lim, Rebecca
    Univ Newcastle, Sch Biomed Sci & Pharm, Callaghan, NSW, Australia;Hunter Med Res Inst, Callaghan, NSW, Australia.
    Lipski, Janusz
    Univ Auckland, Fac Med & Hlth Sci, Auckland, New Zealand.
    Gravina, Fernanda S.
    Univ Newcastle, Sch Biomed Sci & Pharm, Callaghan, NSW, Australia;Hunter Med Res Inst, Callaghan, NSW, Australia.
    Brichta, Alan M.
    Univ Newcastle, Sch Biomed Sci & Pharm, Callaghan, NSW, Australia;Hunter Med Res Inst, Callaghan, NSW, Australia.
    Callister, Robert J.
    Univ Newcastle, Sch Biomed Sci & Pharm, Callaghan, NSW, Australia;Hunter Med Res Inst, Callaghan, NSW, Australia.
    Leão, Richardson N
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Univ Fed Rio Grande do Norte, Brain Inst, Natal, RN, Brazil.
    van Helden, Dirk F.
    Univ Newcastle, Sch Biomed Sci & Pharm, Callaghan, NSW, Australia;Hunter Med Res Inst, Callaghan, NSW, Australia.
    Crosstalk between mitochondria, calcium channels and actin cytoskeleton modulates noradrenergic activity of locus coeruleus neurons2019In: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 149, no 4, p. 471-487Article in journal (Refereed)
    Abstract [en]

    Locus coeruleus (LC) is the name of a group of large sized neurons located at the brain stem, which provides the main source of noradrenaline to the central nervous system, virtually, innervating the whole brain. All noradrenergic signalling provided by this nucleus is dependent on an intrinsic pacemaker process. Our study aims to understand how noradrenergic neurons finely tune their pacemaker processes and regulate their activities. Here we present that mitochondrial perturbation in the LC from mice, inhibits spontaneous firing by a hyperpolarizing response that involves Ca2+ entry via L-type Ca2+ channels and the actin cytoskeleton. We found that pharmacological perturbation of mitochondria from LC neurons using the protonophore carbonyl cyanide m-chlorophenylhydrazone (CCCP), induced a dominant hyperpolarizing response when electrophysiological approaches were performed. Surprisingly, the CCCP-induced hyperpolarizing response was dependent on L-type Ca2+ channel-mediated Ca2+ entry, as it was inhibited by: the removal of extracellular Ca2+; the addition of Cd2+; nifedipine or nicardipine; but not by the intracellular dialysis with the Ca2+ chelator 1,2-Bis(2-Aminophenoxy)ethane-N,N,N ',N '-tetraacetic acid, the latter indicating that the response was not because of a global change in [Ca2+](c) but does not exclude action at intracellular microdomains. Further to this, the incubation of slices with cytochalasin D, an agent that depolymerises the actin cytoskeleton, inhibited the hyperpolarizing response indicating an involvement of the actin cytoskeleton. The data are consistent with the hypothesis that there is a crosstalk between mitochondria and L-type Ca2+ channels leading to modulation of noradrenergic neuronal activity mediated by the actin cytoskeleton. Open Science Badges This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at.

  • 3.
    Garcia-Bennett, Alfonso E.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Kozhevnikova, Mariya
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    König, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Zhou, Chunfang
    Leao, Richardson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Knöpfel, Thomas
    Pankratova, Stanislava
    Trolle, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Berezin, Vladimir
    Bock, Elisabeth
    Aldskogius, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Kozlova, Elena N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Delivery of Differentiation Factors by Mesoporous Silica Particles Assists Advanced Differentiation of Transplanted Murine Embryonic Stem Cells2013In: Stem Cells Translational Medicine, ISSN 2157-6564, E-ISSN 2157-6580, Vol. 2, no 11, p. 906-915Article in journal (Refereed)
    Abstract [en]

    Stem cell transplantation holds great hope for the replacement of damaged cells in the nervous system. However, poor long-term survival after transplantation and insufficiently robust differentiation of stem cells into specialized cell types in vivo remain major obstacles for clinical application. Here, we report the development of a novel technological approach for the local delivery of exogenous trophic factor mimetics to transplanted cells using specifically designed silica nanoporous particles. We demonstrated that delivering Cintrofin and Gliafin, established peptide mimetics of the ciliary neurotrophic factor and glial cell line-derived neurotrophic factor, respectively, with these particles enabled not only robust functional differentiation of motor neurons from transplanted embryonic stem cells but also their long-term survival in vivo. We propose that the delivery of growth factors by mesoporous nanoparticles is a potentially versatile and widely applicable strategy for efficient differentiation and functional integration of stem cell derivatives upon transplantation.

  • 4.
    Hilscher, Markus M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Leao, Katarina E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Leao, Richardson N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Synchronization through nonreciprocal connections in a hybrid hippocampus microcircuit2013In: Frontiers in Neural Circuits, ISSN 1662-5110, E-ISSN 1662-5110, Vol. 7, p. 120-Article in journal (Refereed)
    Abstract [en]

    Synchronization among neurons is thought to arise from the interplay between excitation and inhibition; however, the connectivity rules that contribute to synchronization are still unknown. We studied these issues in hippocampal CA1 microcircuits using paired patch clamp recordings and real time computing. By virtually connecting a model interneuron with two pyramidal cells (PCs), we were able to test the importance of connectivity in synchronizing pyramidal cell activity. Our results show that a circuit with a nonreciprocal connection between pyramidal cells and no feedback from PCs to the virtual interneuron produced the greatest level of synchronization and mutual information between PC spiking activity. Moreover, we investigated the role of intrinsic membrane properties contributing to synchronization where the application of a specific ion channel blocker, ZD7288 dramatically impaired PC synchronization. Additionally, background synaptic activity, in particular arising from NMDA receptors, has a large impact on the synchrony observed in the aforementioned circuit. Our results give new insights to the basic connection paradigms of microcircuits that lead to coordination and the formation of assemblies.

  • 5.
    Hilscher, Markus M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics. Univ Fed Rio Grande do Norte, Inst Brain, Natal, RN, Brazil..
    Leão, Richardson N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics. Univ Fed Rio Grande do Norte, Inst Brain, Natal, RN, Brazil..
    Edwards, Steven J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Leão, Katarina E.
    Univ Fed Rio Grande do Norte, Inst Brain, Natal, RN, Brazil..
    Kullander, Klas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Chrna2-Martinotti Cells Synchronize Layer 5 Type A Pyramidal Cells via Rebound Excitation2017In: PLoS biology, ISSN 1544-9173, E-ISSN 1545-7885, Vol. 15, no 2, article id e2001392Article in journal (Refereed)
    Abstract [en]

    Martinotti cells are the most prominent distal dendrite-targeting interneurons in the cortex, but their role in controlling pyramidal cell ( PC) activity is largely unknown. Here, we show that the nicotinic acetylcholine receptor alpha 2 subunit (Chrna2) specifically marks layer 5 (L5) Martinotti cells projecting to layer 1. Furthermore, we confirm that Chrna2-expressing Martinotti cells selectively target L5 thick-tufted type A PCs but not thin-tufted type B PCs. Using optogenetic activation and inhibition, we demonstrate how Chrna2-Martinotti cells robustly reset and synchronize type A PCs via slow rhythmic burst activity and rebound excitation. Moreover, using optical feedback inhibition, in which PC spikes controlled the firing of surrounding Chrna2-Martinotti cells, we found that neighboring PC spike trains became synchronized by Martinotti cell inhibition. Together, our results show that L5 Martinotti cells participate in defined cortical circuits and can synchronize PCs in a frequency-dependent manner. These findings suggest that Martinotti cells are pivotal for coordinated PC activity, which is involved in cortical information processing and cognitive control.

  • 6.
    Leao, Richardson N
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Targino, Zé Henrique
    Colom, Luis V
    Fisahn, André
    Interconnection and Synchronization of Neuronal Populations in the Mouse Medial Septum/Diagonal Band of Brocca2015In: Journal of Neurophysiology, ISSN 0022-3077, E-ISSN 1522-1598, Vol. 113, no 3, p. 971-980Article in journal (Refereed)
    Abstract [en]

    The medial septum/diagonal band of Broca (MS/DBB) is crucial for hippocampal theta rhythm generation (4-12Hz). However, the mechanisms behind theta rhythmogenesis are still under debate. The MS/DBB consists, in its majority, of three neuronal populations that use either acetylcholine, GABA or glutamate as neurotransmitters. While the firing patterns of septal neurons enable the MS/DBB to generate rhythmic output critical for the generation of the hippocampal theta rhythm, the ability to synchronize these action potentials is dependent on the interconnectivity between the three major MS/DBB neuronal populations. Yet little is known about intraseptal connections. Here we assess the connectivity between pairs of MS/DBB neurons using paired patch-clamp recordings. We found that glutamatergic and GABAergic neurons provide intraseptal connections and produce sizable currents in MS/DBB postsynaptic cells. We also analyzed linear and non-linear relationships between the action potentials fired by pairs of neurons belonging to various MS/DBB neuronal populations. Our results show that while the synchrony index for action potential firing was significantly higher in pairs of GABAergic neurons coherence of action potential firing in the theta range was similarly low in all pairs analyzed. Recurrence analysis demonstrated that individual action potentials were more recurrent in cholinergic neurons than other cell types. Implementing sparse connectivity in a computer model of the MS/DBB network reproduced our experimental data. We conclude that the interplay between the intrinsic membrane properties of different MS/DBB neuronal populations and the connectivity amongst these populations underlies the ability of the MS/DBB network to critically contribute to hippocampal theta rhythmogenesis.

  • 7.
    Leão, Richardson N.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Colom, Luis V.
    Borgius, Lotta
    Kiehn, Ole
    Fisahn, Andre
    Medial septal dysfunction by A beta-induced KCNQ channel-block in glutamatergic neurons2012In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 33, no 9, p. 2046-2061Article in journal (Refereed)
    Abstract [en]

    Amyloid beta (A beta) peptides play a central role in the pathophysiology of Alzheimer's disease (AD). The cellular mechanisms underlying A beta toxicity, however, are poorly understood. Here we show that A beta 25-35 and A beta 1-40 acutely and differentially affect the characteristics of 3 classes of medial septum (MS) neurons in mice. In glutamatergic neurons A beta increases firing frequency and blocks the A-and the M-current (I-A and I-M, respectively). While the I-A block is similar in other MS neuron classes, the block of I-M is specific to glutamatergic neurons. I-M block and a simulated A beta block mimic the A beta-induced increase in spontaneous firing in glutamatergic neurons. Calcium imaging shows that under control conditions glutamatergic neurons rarely fire while nonglutamatergic neurons fire coherently at theta frequencies. A beta increases the firing rate of glutamatergic neurons while nonglutamatergic neurons lose theta firing coherence. Our results demonstrate that A beta-induced dysfunction of glutamatergic neurons via I-M decrease diminishes MS rhythmicity, which may negatively affect hippocampal rhythmogenesis and underlie the memory loss observed in Alzheimer's disease.

  • 8.
    Leão, Richardson Naves
    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.
    Leão, Katarina E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Munguba, H.
    Gezelius, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Enjin, Anders
    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.
    Eriksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Loew, L. M.
    Tort, A. B. L.
    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.
    OLM interneurons differentially modulate CA3 and entorhinal inputs to hippocampal CA1 neurons2012In: Nature Neuroscience, ISSN 1097-6256, E-ISSN 1546-1726, Vol. 15, no 11, p. 1524-1530Article in journal (Refereed)
    Abstract [en]

    The vast diversity of GABAergic interneurons is believed to endow hippocampal microcircuits with the required flexibility for memory encoding and retrieval. However, dissection of the functional roles of defined interneuron types has been hampered by the lack of cell-specific tools. We identified a precise molecular marker for a population of hippocampal GABAergic interneurons known as oriens lacunosum-moleculare (OLM) cells. By combining transgenic mice and optogenetic tools, we found that OLM cells are important for gating the information flow in CA1, facilitating the transmission of intrahippocampal information (from CA3) while reducing the influence of extrahippocampal inputs (from the entorhinal cortex). Furthermore, we found that OLM cells were interconnected by gap junctions, received direct cholinergic inputs from subcortical afferents and accounted for the effect of nicotine on synaptic plasticity of the Schaffer collateral pathway. Our results suggest that acetylcholine acting through OLM cells can control the mnemonic processes executed by the hippocampus.

  • 9.
    Lima da Cruz, Rafael Vitor
    et al.
    Univ Fed Rio Grande do Norte, Brain Inst, Neurodynam Lab, Natal, RN, Brazil.
    Moulin, Thiago C.
    Univ Fed Rio de Janeiro, Inst Med Biochem, Rio De Janeiro, Brazil.
    Petiz, Lyvia Lintzmaier
    Univ Fed Rio Grande do Norte, Brain Inst, Neurodynam Lab, Natal, RN, Brazil.
    Leão, Richardson N
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics. Univ Fed Rio Grande do Norte, Brain Inst, Neurodynam Lab, Natal, RN, Brazil.
    A Single Dose of 5-MeO-DMT Stimulates Cell Proliferation, Neuronal Survivability, Morphological and Functional Changes in Adult Mice Ventral Dentate Gyrus2018In: Frontiers in Molecular Neuroscience, ISSN 1662-5099, Vol. 11, article id 312Article in journal (Refereed)
    Abstract [en]

    The subgranular zone (SGZ) of dentate gyrus (DG) is one of the few regions in which neurogenesis is maintained throughout adulthood. It is believed that newborn neurons in this region encode temporal information about partially overlapping contextual memories. The 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a naturally occurring compound capable of inducing a powerful psychedelic state. Recently, it has been suggested that DMT analogs may be used in the treatment of mood disorders. Due to the strong link between altered neurogenesis and mood disorders, we tested whether 5-MeO-DMT is capable of increasing DG cell proliferation. We show that a single intracerebroventricular (ICV) injection of 5-MeO-DMT increases the number of Bromodeoxyuridine (BrdU+) cells in adult mice DG. Moreover, using a transgenic animal expressing tamoxifen-dependent Cre recombinase under doublecortin promoter, we found that 5 Meo-DMT treated mice had a higher number of newborn DG Granule cells (GC). We also showed that these DG GC have more complex dendritic morphology after 5-MeO-DMT. Lastly, newborn GC treated with 5-MeO-DMT, display shorter afterhyperpolarization (AHP) potentials and higher action potential (AP) threshold compared. Our findings show that 5-MeO-DMT affects neurogenesis and this effect may contribute to the known antidepressant properties of DMT-derived compounds.

  • 10.
    Mikulovic, Sanja
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Pupe, Stéfano
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Peixoto, Helotn Maia
    Do Nascimiento, George
    Kullander, Klas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Tort, Adriano
    Leao, Richardson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    On the photovoltaic effect in localfield potential recordings2016In: Neurophotonics, ISSN 2329-423X, Vol. 3, no 1, article id 015002Article in journal (Refereed)
    Abstract [en]

    ptogenetics allows light activation of genetically defined cell populations and the study of their link to specific brain functions. While it is a powerful method that has revolutionized neuroscience in the last decade, the shortcomings of directly stimulating electrodes and living tissue with light have been poorly characterized. Here, we assessed the photovoltaic effects in local field potential (LFP) recordings of the mouse hippocampus. We found that light leads to several artifacts that resemble genuine LFP features in animals with no opsin expression, such as stereotyped peaks at the power spectrum, phase shifts across different recording channels, coupling between low and high oscillation frequencies, and sharp signal deflections that are detected as spikes. Further, we tested how light stimulation affected hippocampal LFP recordings in mice expressing channelrhodopsin 2 in parvalbumin neurons (PV/ChR2 mice). Genuine oscillatory activity at the frequency of light stimulation could not be separated from light-induced artifacts. In addition, light stimulation in PV/ChR2 mice led to an overall decrease in LFP power. Thus, genuine LFP changes caused by the stimulation of specific cell populations may be intermingled with spurious changes caused by photovoltaic effects. Our data suggest that care should be taken in the interpretation of electrophysiology experiments involving light stimulation.

  • 11.
    Mikulovic, Sanja
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Restrepo, Carlos Ernesto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Siwani, Samer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Bauer, Pavol
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Scientific Computing. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computational Science.
    Johann, Stefano Pupe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Tort, Adriano B. L.
    Kullander, Klas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Leão, Richardson N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Ventral hippocampal OLM cells control type 2 theta oscillations and response to predator odor2018In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, p. 3638:1-15, article id 3638Article in journal (Refereed)
  • 12.
    Mikulovic, Sanja
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Restrepo, Ernesto C.
    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.
    Kullander, Klas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Leao, Richardson N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Novel markers for OLM interneurons in the hippocampus2015In: Frontiers in Cellular Neuroscience, ISSN 1662-5102, E-ISSN 1662-5102, Vol. 9, article id 201Article in journal (Other academic)
  • 13.
    Nordenankar, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Smith-Anttila, Casey J A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Schweizer, Nadine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Viereckel, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Birgner, Carolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Mejia-Toiber, Jana
    Morales, Marisela
    Leao, Richardson Naves
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Wallén-Mackenzie, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Increased hippocampal excitability and impaired spatial memory function in mice lacking VGLUT2 selectively in neurons defined by tyrosine hydroxylase promoter activity2015In: Brain Structure and Function, ISSN 1863-2653, E-ISSN 1863-2661, Vol. 220, no 4, p. 2171-2190Article in journal (Refereed)
    Abstract [en]

    Three populations of neurons expressing the vesicular glutamate transporter 2 (Vglut2) were recently described in the A10 area of the mouse midbrain, of which two populations were shown to express the gene encoding, the rate-limiting enzyme for catecholamine synthesis, tyrosine hydroxylase (TH).One of these populations ("TH-Vglut2 Class1") also expressed the dopamine transporter (DAT) gene while one did not ("TH-Vglut2 Class2"), and the remaining population did not express TH at all ("Vglut2-only"). TH is known to be expressed by a promoter which shows two phases of activation, a transient one early during embryonal development, and a later one which gives rise to stable endogenous expression of the TH gene. The transient phase is, however, not specific to catecholaminergic neurons, a feature taken to advantage here as it enabled Vglut2 gene targeting within all three A10 populations expressing this gene, thus creating a new conditional knockout. These knockout mice showed impairment in spatial memory function. Electrophysiological analyses revealed a profound alteration of oscillatory activity in the CA3 region of the hippocampus. In addition to identifying a novel role for Vglut2 in hippocampus function, this study points to the need for improved genetic tools for targeting of the diversity of subpopulations of the A10 area.

  • 14.
    Patra, Kalicharan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Lyons, David J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Bauer, Pavol
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Hilscher, Markus M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Sharma, Swati
    Leão, Richardson N
    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.
    A role for solute carrier family 10 member 4, or vesicular aminergic-associated transporter, in structural remodelling and transmitter release at the mouse neuromuscular junction.2015In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 41, no 3, p. 316-327Article in journal (Refereed)
    Abstract [en]

    The solute carrier and presynaptic vesicle protein solute carrier family 10 member 4, or vesicular aminergic-associated transporter (VAAT), was recently proven to have a modulatory role in central cholinergic signalling. It is currently unknown whether VAAT also affects peripheral cholinergic synapses. Here we demonstrated a regulatory role for the presynaptic vesicle protein VAAT in neuromuscular junction (NMJ) development and function. NMJs lacking VAAT had fewer branch points, whereas endplates showed an increased number of islands. Whereas the amplitude of spontaneous miniature endplate potentials in VAAT-deficient NMJs was decreased, the amplitude of evoked endplate potentials and the size of the readily releasable pool of vesicles were both increased. Moreover, VAAT-deficient NMJs displayed aberrant short-term synaptic plasticity with enhanced synaptic depression in response to high-frequency stimulation. Finally, the transcript levels of cholinergic receptor subunits in VAAT-deficient muscles were increased, indicating a compensatory postsynaptic sensitization. Our results suggested that VAAT modulates NMJ transmission efficiency and, as such, may represent a novel target for treatment of disorders affecting motor neurons.

  • 15. Peixoto, Helton M.
    et al.
    Munguba, Hermany
    Cruz, Rossana M. S.
    Guerreiro, Ana M. G.
    Leao, Richardson N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Automatic tracking of cells for video microscopy in patch clamp experiments2014In: Biomedical engineering online, ISSN 1475-925X, E-ISSN 1475-925X, Vol. 13, p. 78-Article in journal (Refereed)
    Abstract [en]

    Background: Visualisation of neurons labeled with fluorescent proteins or compounds generally require exposure to intense light for a relatively long period of time, often leading to bleaching of the fluorescent probe and photodamage of the tissue. Here we created a technique to drastically shorten light exposure and improve the targeting of fluorescent labeled cells that is specially useful for patch-clamp recordings. We applied image tracking and mask overlay to reduce the time of fluorescence exposure and minimise mistakes when identifying neurons. Methods: Neurons are first identified according to visual criteria (e.g. fluorescence protein expression, shape, viability etc.) and a transmission microscopy image Differential Interference Contrast (DIC) or Dodt contrast containing the cell used as a reference for the tracking algorithm. A fluorescence image can also be acquired later to be used as a mask (that can be overlaid on the target during live transmission video). As patch-clamp experiments require translating the microscope stage, we used pattern matching to track reference neurons in order to move the fluorescence mask to match the new position of the objective in relation to the sample. For the image processing we used the Open Source Computer Vision (OpenCV) library, including the Speeded-Up Robust Features (SURF) for tracking cells. The dataset of images (n = 720) was analyzed under normal conditions of acquisition and with influence of noise (defocusing and brightness). Results: We validated the method in dissociated neuronal cultures and fresh brain slices expressing Enhanced Yellow Fluorescent Protein (eYFP) or Tandem Dimer Tomato (tdTomato) proteins, which considerably decreased the exposure to fluorescence excitation, thereby minimising photodamage. We also show that the neuron tracking can be used in differential interference contrast or Dodt contrast microscopy. Conclusion: The techniques of digital image processing used in this work are an important addition to the set of microscopy tools used in modern electrophysiology, specially in experiments with neuron cultures and brain slices.

  • 16. Rattay, F.
    et al.
    Paredes, L. P.
    Naves Leao, Richardson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Strength-duration relationship for intra-versus extracellular stimulation with microelectrodes2012In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 214, p. 1-13Article in journal (Refereed)
    Abstract [en]

    Chronaxie, a historically introduced excitability time parameter for electrical stimulation, has been assumed to be closely related to the time constant of the cell membrane. Therefore, it is perplexing that significantly larger chronaxies have been found for intracellular than for extracellular stimulation. Using compartmental model analysis, this controversy is explained on the basis that extracellular stimulation also generates hyperpolarized regions of the cell membrane hindering a steady excitation as seen in the intracellular case. The largest inside/outside chronaxie ratio for microelectrode stimulation is found in close vicinity of the cell. In the case of monophasic cathodic stimulation, the length of the primarily excited zone which is situated between the hyperpolarized regions increases with electrode-cell distance. For distant electrodes this results in an excitation process comparable to the temporal behavior of intracellular stimulation. Chronaxie also varies along the neural axis, being small for electrode positions at the nodes of Ranvier and axon initial segment and larger at the soma and dendrites. As spike initiation site can change for short and long pulses, in some cases strength-duration curves have a bimodal shape, and thus, they deviate from a classical monotonic curve as described by the formulas of Lapicque or Weiss. (c) 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

  • 17.
    Schweizer, Nadine
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Pupe, Stefano
    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.
    Nordenankar, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Smith-Anttila, Casey J. A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Mahmoudi, Souha
    Andrén, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Dumas, Sylvie
    Rajagopalan, Aparna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Levesque, Daniel
    Leao, Richardson N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Wallén-Mackenzie, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Limiting glutamate transmission in a Vglut2-expressing subpopulation of the subthalamic nucleus is sufficient to cause hyperlocomotion2014In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 111, no 21, p. 7837-7842Article in journal (Refereed)
    Abstract [en]

    The subthalamic nucleus (STN) is a key area of the basal ganglia circuitry regulating movement. We identified a subpopulation of neurons within this structure that coexpresses Vglut2 and Pitx2, and by conditional targeting of this subpopulation we reduced Vglut2 expression levels in the STN by 40%, leaving Pitx2 expression intact. This reduction diminished, yet did not eliminate, glutamatergic transmission in the substantia nigra pars reticulata and entopeduncular nucleus, two major targets of the STN. The knockout mice displayed hyperlocomotion and decreased latency in the initiation of movement while preserving normal gait and balance. Spatial cognition, social function, and level of impulsive choice also remained undisturbed. Furthermore, these mice showed reduced dopamine transporter binding and slower dopamine clearance in vivo, suggesting that Vglut2-expressing cells in the STN regulate dopaminergic transmission. Our results demonstrate that altering the contribution of a limited population within the STN is sufficient to achieve results similar to STN lesions and high-frequency stimulation, but with fewer side effects.

  • 18.
    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.

  • 19.
    Siwani, Samer
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Franca, Arthur S. C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics. Univ Fed Rio Grande do Norte, Brain Inst, BR-59056450 Natal, RN, Brazil;Donders Inst Brain Behav & Cognit, NL-6525 EN Nijmegen, Gelderland, Netherlands.
    Mikulovic, Sanja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Reis, Amilcar
    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. Univ Fed Rio Grande do Norte, Brain Inst, BR-59056450 Natal, RN, Brazil.
    Edwards, Steven J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Leão, Richardson N
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics. Univ Fed Rio Grande do Norte, Brain Inst, BR-59056450 Natal, RN, Brazil.
    Tort, Adriano B. L.
    Univ Fed Rio Grande do Norte, Brain Inst, BR-59056450 Natal, RN, Brazil.
    Kullander, Klas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    OLM alpha 2 Cells Bidirectionally Modulate Learning2018In: Neuron, ISSN 0896-6273, E-ISSN 1097-4199, Vol. 99, no 2, p. 404-412Article in journal (Refereed)
    Abstract [en]

    Inhibitory interneurons participate in mnemonic processes. However, defined roles for identified interneuron populations are scarce. A subpopulation of oriens lacunosum-moleculare (OLM) interneurons genetically defined by the expression of the nicotinic receptor alpha 2 subunit has been shown to gate information carried by either the temporoammonic pathway or Schaffer collaterals in vitro. Here we set out to determine whether selective modulation of OLM alpha 2 cells in the intermediate CA1 affects learning and memory in vivo. Our data show that intermediate OLM alpha 2 cells can either enhance (upon their inhibition) or impair (upon their activation) object memory encoding in freely moving mice, thus exerting bidirectional control. Moreover, we find that OLM alpha 2 cell activation inhibits fear-related memories and that OLM alpha 2 cells respond differently to nicotine in the dorsoventral axis. These results suggest that intermediate OLM alpha 2 cells are an important component in the CA1 microcircuit regulating learning and memory processes.

  • 20.
    Wallen-Mackenzie, Åsa
    et al.
    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.
    Restrepo, Ernesto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Johann, Stefano Pupe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Perland, Emelie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Nordenankar, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Kullander, Klas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Alsiö, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Leao, Richardson Naves
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Targeting VGLUT2 in dopamine neurons affects the brain reward system2012In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 22, no S2, p. S128-S129Article in journal (Other academic)
  • 21.
    Winne, Jessica
    et al.
    Univ Fed Rio Grande do Norte, Inst Brain, Neurodynam Lab, Natal, RN, Brazil.
    Franzon, Rafael
    Univ Fed Rio Grande do Norte, Inst Brain, Neurodynam Lab, Natal, RN, Brazil.
    de Miranda, Aron
    Univ Fed Rio Grande do Norte, Inst Brain, Neurodynam Lab, Natal, RN, Brazil.
    Malfatti, Thawann
    Univ Fed Rio Grande do Norte, Inst Brain, Neurodynam Lab, Natal, RN, Brazil.
    Patriota, Joao
    Univ Fed Rio Grande do Norte, Inst Brain, Ave Nascimento de Castro 2155, Natal, RN, Brazil.
    Mikulovic, Sanja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Leao, Katarina E.
    Univ Fed Rio Grande do Norte, Inst Brain, Neurodynam Lab, Natal, RN, Brazil.
    Leão, Richardson N
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Univ Fed Rio Grande do Norte, Inst Brain, Neurodynam Lab, Natal, RN, Brazil.
    Salicylate induces anxiety-like behavior and slow theta oscillation and abolishes the relationship between running speed and fast theta oscillation frequency2019In: Hippocampus, ISSN 1050-9631, E-ISSN 1098-1063, Vol. 29, no 1, p. 15-25Article in journal (Refereed)
    Abstract [en]

    Salicylate intoxication is a cause of tinnitus in humans and it is often used to produce tinnitus-like perception in animal models. Here, we assess whether salicylate induces anxiety-like electrophysiological and behavioral signs. Using microwire electrode arrays, we recorded local field potential in the ventral and, in some experiments dorsal hippocampus, in an open field arena 1 hr after salicylate (300 mg/kg) injection. We found that animals treated with salicylate moved dramatically less than saline treated animals. Salicylate-treated animals showed a strong 4-6 Hz (type 2) oscillation in the ventral hippocampus (with smaller peaks in dorsal hippocampus electrodes). Coherence in the 4-6 Hz-theta band was low in the ventral and dorsal hippocampus when compared to movement-related theta coherence (7-10 Hz). Moreover, movement related theta oscillation frequency decreased and its dependency on running speed was abolished. Our results suggest that salicylate-induced theta is mostly restricted to the ventral hippocampus. Slow theta has been classically associated to anxiety-like behaviors. Here, we show that salicylate application can consistently generate low frequency theta in the ventral hippocampus. Tinnitus and anxiety show strong comorbidity and the increase in ventral hippocampus low frequency theta could be part of this association.

  • 22.
    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.

1 - 22 of 22
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