CR11 UH.NEUROSCI - Helsingin yliopisto (Finland)

CR11 UH.NEUROSCI - Helsingin yliopisto (Finland)

Prof. Anna-Elina Lehesjoki, ph. +358-9-19125072, fax +358-9-19125073, Anna-elina.lehesjoki@helsinki.fi

Two departments of the Helsingin yliopisto (University of Helsinki) will be involved in the frame of the project:

Between this two departments, the Neuroscience Center will act, only from an administrative point of view, as partner with the European Commission. For this purpose, Prof. Anna-Elina Lehesjoki will be the person in charge for the project representing the University of Helsinki.

Expertise and current research performed: The group belongs to the Center of Excellence in Complex Disease Genetics of the Academy of Finland and the Nordic Center of Excellence in Disease Genetics, which aim to identify predisposing genes and risk alleles for common diseases. The unit has a strong track record in elucidating the molecular background of several, both single gene and complex disorders. The group has three lines of research: 1) Analysis of disease mechanisms in two symptomatic epilepsy phenotypes using cellular and animal models (mouse, zebrafish, fruit fly), 2) identification of novel genes underlying human single gene inherited diseases, 3) identification of susceptibility genes for epilepsy phenotypes with complex inheritance. The group has identified and collected samples from Finnish pedigrees with autosomal dominant idiopathic epilepsy. Positional cloning in two loci and analysis of genome scan data in three families is ongoing. In order to tackle the molecular genetic basis of complex epilepsies in

Finland

, the collection of patient and family material displaying idiopathic generalized epilepsy has been initiated in collaboration with clinical investigators in several Finnish hospitals.

Facilities/Equipment: The Unit is equipped with: ABI 3730 automatic capillary sequencer, ABI PRISM® 7900HT Sequence Detection System, TECAN Miniprep 75/1 pipeting robot, The Transgenomic WAVE® dHPLC machine. The group has access to in house core facilities: large scale DNA extraction unit with an automated Gentra DNA extraction equipment and liquid handling robots, Sequenom MALDI-TOF mass array instrument, Affymetrix gene chip system.

Principal investigator: Anna-Elina Lehesjoki (F). MD, PhD, is Professor and Research Director at the Neuroscience Center of the University of Helsinki and Head of the Folkhälsan Institute of Genetics in Biomedicum Helsinki. Dr. Lehesjoki's has been focused on the identification of disease genes in neurological disorders, including epilepsy. Her current research interest are to understand disease mechanisms in two symptomatic epilepsy syndromes and to identify new epilepsy genes and predisposing genes for epilepsy with complex inheritance. She coordinates and supervises the proposed work within SP1 in

Finland

Auli Sirén (F). MD, is a specialist in pediatric neurology and is completing her PhD thesis on molecular aspects of epilepsy. She works part time as a pediatric neurologist in the Tampere University Hospital and as a clinical coordinator for the epilepsy genetics project in the group of Dr. Lehesjoki. She has worked in the field of epilepsy genetics since 1999. She coordinates the clinical data collection (WP1, WP2) and participates in design and data analysis of the molecular genetic work (WP3) in SP1. Anne Polvi (F), PhD in genetics, has worked as a postdoctoral fellow in the group since 2006. She did her thesis in 1998 at the university of Helsinki and have previous experience studying genetics of complex diseases: celiac disease and asthma. She is coordinating the sequencing part in the WP3 subproject and supervising technicians in laboratory work. She also performs the analysis and reporting. Hanna Olanne (F). Technician. Graduated as a laboratory technician in May 2004 after which she has worked as a technician in the epilepsy group. She will be responsible for the molecular genetic laboratory work (WP3) in SP1.

1. Hennah W, Tuulio-Henriksson A, Paunio T, Ekelund J, Varilo T, Partonen T, Cannon TD, Lonnqvist J, Peltonen L. (2005) A haplotype within the DISC1 gene is associated with visual memory functions in families with a high density of schizophrenia. Mol Psychiatry.

2. Ranta S, Topcu M, Tegelberg S, TanH, Ustubutun A, Saatci I, Mitchell WA, MoleSE, LehesjokiA-E. (2004) Variant late infantile neuronal ceroid lipofuscinosis in a subset of Turkish patients is allelic to Northern epilepsy. Hum Mutat 23:300-305.

3. Robinson R, Taske N, Heils A, Sander T, Whitehouse W, Goutières F, Aicardi J, Lehesjoki A-E, Siren A, Laue Friis M, Kjeldsen MJ, Panayiotopoulos C, Kennedy C, Ferrie C, Rees M, Gardiner R.M. (2002) Linkage analysis between childhood absence epilepsy and genes encoding GABA(A) and GABA(B) receptors, voltage-dependent calcium channels, and the ECA1 region on chromosome 8q. Epilepsy Res 48:169-179.

4. Ranta S, Zhang Y, Ross B, Lonka L, Takkunen E, Messer A, Sharp J, Wheeler R, More S, Liu W, Soares MB, de Fatima Bonaldo M, Hirvasniemi A, de la Chapelle A, Gilliam TC, Lehesjoki A-E. (1999) The neuronal ceroid lipofuscinosis in human EPMR and mnd mutant mice are associated with mutations in CLN8. Nature Genet 23:233-236.

5. Pennacchio LA, Lehesjoki A-E, Stone NE, Willour VL, Virtaneva K, Miao J, D'Amato E, Ramirez L, Faham M, Koskiniemi M, Warrington J, Norio R, de la Chapelle A, Cox DR, Myers RM. (1996) Mutations in the gene encoding cystatin B cause progressive myoclonus epilepsy (EPM1). Science 271:1731-1734.

Expertise and current research performed: The laboratory belongs to the Finnish Academy CoE in Molecular Neurobiology and to the Nordic CoE WIRED (on water/ion-related diseases). The team investigates the biophysical, molecular and network mechanisms underlying neuronal communication and plasticity in the normal and epileptic brain. The research strategy is based on using a number of electrophysiological and molecular biological techniques on research models ranging from cloned receptors/carriers and isolated or cultured neurons to brain tissue slices, and to the rat and human brain in vivo. The group has identified a number of basic mechanisms in various aspects of neuronal signalling, development, plasticity, and hyperexcitability. The current research activities include: 1. Role of anion-regulatory molecules in neuronal maturation, injury and epilepsy. 2. Anion-regulatory molecules (especially CAVII) as targets of novel anticonvulsant drugs. 3. Spontaneous network activity during development and epilepsy: ionic, pacemaker and network mechanisms. 4. Physiology and pathophysiology of slow endogenous activity in the immature rat and human cortex in vivo. 5. Development of DC-EEG for routine clinical applications.

Facilities/Equipment Whole-cell, perforated-patch clamp and ion-selective microelectrodes are used in 7 electrophysiological set ups, with infrared visualization and confocal microscopy. The lab has KCC2-/- and NKCC1-/- mice. In vivo recordings in rats are done with chronically implanted intrahippocampal and intracortical electrodes; and in human epilepsy patients using novel DC-EEG technologies.

Principal investigator: Kai Kaila (M) PhD, Professor of the Academy of Finland (1996-), Head of the Laboratory of Neurobiology in the Department of Biological and Environmental Sciences; and Adjunct Professor in the Neuroscience Center of the University of Helsinki. Working in the field since 1982. Research interests: the biophysical, molecular and network mechanisms underlying neuronal communication and plasticity in the developing and epileptic brain.

Claudio Rivera (M). PhD, Senior Researcher in the Institute of Biotechnology, University of Helsinki. Working in the field since 1990. Research interests: mechanisms involved in the interplay between intracellular chloride regulation and neurotrophic factors in clinically important paradigms for epilepsy and CNS injury. Juha Voipio (M). PhD, Professor of Electrophysiology, Senior Researcher in the Department of Biological and Environmental Sciences, University of Helsinki. Working in the field since 1988. Research interests are: Volume transmission mediated by K+ and acid/base species in the brain: role in synaptic function and dysfunction; and DC-EEG. Junko Yamada (F). PhD, post doctoral researcher in the Department of Biological and Environmental Sciences, University of Helsinki. Past position that are relevant for the project. Working in the field since 1998, training in area in Atsuo Fukuda’s lab. Research interests are: Role of chloride transporters KCC2 and NKCC1 in neuronal plasticity in the rodent hippocampus. Sampsa Sipila (M). M.D. PhD student, Dept Biological and Env., Univ. Helsinki. Research interest: Mechanisms of spontaneous activity in developing and epileptic hippocampus. Stanislav Khiroug (M). MSc, PhD student, Dept Biological and Env., Univ. Helsinki. Research interests: Ionic modulation of transmitter functions in the hippocampus. Kristiina Huttu (M). MSc, PhD student, Dept Biological and Env., Univ. Helsinki. Research interests: Mechanisms of spontaneous activity in the developing hippocampus and cortex; GABAergic transmission in the immature and epileptic hippocampus. Ilya Kirilkin (M). MSc, PhD student, Dept Biological and Env., Univ. Helsinki. Research interests: Mechanisms of febrile seizures. Mari Palviainen (F). Bioanalyst, Dept Biological and Env., Univ. Helsinki. Expertise in molecular biological and histochemical techniques. Working in the field since 1998.

1. Vanhatalo S, Palva JM, Holmes MD, Miller JW, Voipio J and Kaila K. (2004) Infraslow oscillations modulate excitability and interictal epileptic activity in the human cortex during sleep. Proc Natl Acad Sci USA 101(14):5053-5057.

2. Rivera C, Voipio J, Thomas-Crusells J, Li H, Emri Z, Sipila S, Payne JA, Minichiello L, Saarma M, Kaila K. (2004) Mechanism of activity-dependent downregulation of the neuron-specific K-Cl^- cotransporter KCC2. J Neurosci. 24:4683-4691.

3. Ruusuvuori E, Li H, Huttu K, Palva JM, Smirnov S, Rivera C, Kaila K, Voipio J. (2004). Carbonic anhydrase isoform VII acts as a molecular switch in the development of synchronous Gamma-frequency firing of hippocampal CA1 pyramidal cells. J Neurosci. 24:2699-2707.

4. Rivera,C., Voipio,J., Payne,J.A., Ruusuvuori,E., Lahtinen,H., Lamsa,K., Pirvola,U., Saarma,M. & Kaila,K. (1999) The K+/Cl- co-transporter KCC2 renders GABA hyperpolarizing during neuronal maturation. Nature, 397, 251-255.

5. Kaila K., Voipio J. (1987) Postsynaptic fall in intracellular pH induced by GABA-activated bicarbonate conductance. Nature 330: 163-165.