The role of NMDA receptor subunits in the regulation of synaptic plasticity in dorsomedial striatum in a model of paroxysmal dystonia [Elektronische Ressource] / Josef Aaron Avshalomov
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The role of NMDA receptor subunits in the regulation of synaptic plasticity in dorsomedial striatum in a model of paroxysmal dystonia [Elektronische Ressource] / Josef Aaron Avshalomov

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From the Department of Physiology, University of Rostock, Germany Head of Department: Prof. Dr. Rüdiger Köhling The role of NMDA receptor subunits in the regulation of synaptic plasticity in dorsomedial striatum in a model of paroxysmal dystonia Dissertation to obtain the academic degree of Doctor of Natural Sciences (doctor rerum naturalium) presented to the Faculty of Matematics and Natural Sciences at University of Rostock, Germany from MSc in Neuroscience and MSc in Advanced Neuro and Molecular Pharmacology Josef Aaron Avshalomov. born in 27.01.1975 in Baku (USSR) Rostock, November 2007 urn:nbn:de:gbv:28-diss2008-0085-5 I would like to dedicate my PhD research thesis to Dr Steven D. Kerr (Department of Pharmacology and Toxicology, Otago University, New Zealand) who has showed me the way to my science. i Acknowledgment I would like to thank Professor Rüdiger Köhling for being a superb supervisor and for give to me an opportunity to undertake this project in the Department of Physiology at Rostock University. I would like to thank Professor Dieter Weiss for acting as a co-supervisor. Many thanks also to Dr Timo Kirschstein, and to Dr Gleb Barmashenko for their great suggestions. Special thanks to Professor David Lovinger from National Institute on Alcohol Abuse and Alcoholism, National Institute of Health, Bethesda, Maryland.

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Published 01 January 2008
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From the Department of Physiology, University of Rostock, Germany
Head of Department: Prof. Dr. Rüdiger Köhling


The role of NMDA receptor subunits in the regulation of synaptic
plasticity in dorsomedial striatum in a model of paroxysmal
dystonia


Dissertation

to obtain the academic degree of Doctor of Natural Sciences
(doctor rerum naturalium)


presented to the
Faculty of Matematics and Natural Sciences at University of Rostock, Germany


from MSc in Neuroscience and MSc in Advanced Neuro and Molecular Pharmacology
Josef Aaron Avshalomov.
born in 27.01.1975 in Baku (USSR)




Rostock, November 2007

urn:nbn:de:gbv:28-diss2008-0085-5








I would like to dedicate my PhD research thesis to Dr Steven D. Kerr (Department of
Pharmacology and Toxicology, Otago University, New Zealand) who has showed me the way
to my science.






















i Acknowledgment


I would like to thank Professor Rüdiger Köhling for being a superb supervisor and for give to
me an opportunity to undertake this project in the Department of Physiology at Rostock
University. I would like to thank Professor Dieter Weiss for acting as a co-supervisor. Many
thanks also to Dr Timo Kirschstein, and to Dr Gleb Barmashenko for their great suggestions.
Special thanks to Professor David Lovinger from National Institute on Alcohol Abuse and
Alcoholism, National Institute of Health, Bethesda, Maryland. I thank also to Professor
Angelika Richter and Dr Melanie Hamann from the Freie Universität Berlin for providing the
hamsters, making possible this PhD project. I wish to acknowledge and to thank to my friend
Robert Schulz for a great support throughout my PhD project at University of Rostock.







Ben Zoma (a Talmudic sage) asks: “Who is wise?”

He answers: “He who learns from every person”.

(Pirke Avot 4:1)










ii

Abstract

szDystonias are movement disorders whose pathomechanism is largely unknown. The dt
dystonic hamster mutant represents a model of primary paroxysmal dystonia, where
alterations of striatal interneuron density and long term potentiation were described (Köhling
et al., 2004, Gernert et al., 2000). In the present thesis, using corticostriatal slices, we explore
in more detail whether long-term potentiation (LTP) and long-term depression (LTD) are
shifted by a) behavioural stimulation or b) ontogenetic maturation using different stimulation
protocols in the cortico-striatal synaptic pathway. The third aim of the thesis was c) to explore
the role of NMDA receptors and their subunits in synaptic plasticity changes occurring with
dystonia. Field extracellular recordings were conducted in dorsomedial striatum, and white
matter was stimulated. Short and long term plasticity as well as input-output relationships
were analysed. The main findings were: a. The occurrence of enhanced synaptic plasticity is
not dependent on behavioural stimulation, while changes in excitability are. b. Ontogenetic
maturation increases the dynamic range of synaptic plasticity under normal conditions, which
is infringed in animals with dystonia, even though the symptoms have remitted. c. In dystonic
tissue, LTP is dependent on NR2A, wheras in normal tissue, it depends on NR2B receptors. In
conclusion, the functional shifts in NR2A vs. NR2B involvement in synaptic corticostriatal
sz plasticity may be instrumental in the pathogenesis of dystonia in the dt model.







iii

Contents

Introduction

Striatum

1.1 Function 2-3

1.2 The cortico-basal ganglia thalamocortical circuit 3-4

1.3 Striatal Neurons 4

1.4 Neurochemistry of the Striatum 4-5


Dystonia

2.1 General Background 6

2.2 Definition and Classification of Dystonia 6-7

2.3 Animal Model of Dystonia (Dystonic Hamsters) 7

2.4 Neuropathology of Dystonia 7-8

Synaptic plasticity

3.1 A brief history of synaptic plasticity 9-10

3.2 Synaptic plasticity in hippocampus 10-11

iv 3.3 Synaptic plasticity in neostriatum 11-13

3.4 Dopamine receptors and LTP in corticostriatal fibers 13-14

3.5 Dopamine receptors and LTD in corticostriatal fibers 14

3.6 Mechanisms Underlying Long-Term Potentiation 16

3.7 NMDA receptor and Long-Term Potentiatio 16-17

3.8 AMPA receptor phopshorylation and synaptic plasticity 17-18

3.9 AMPA receptor subunits and LTP 18-20

3.10 The role of NMDA receptors in Learning and Memory 20-22

Pathophysiology of Dystonia

4.1 Cellular and Molecular Mechanisms in Dystonic Hamster 25


Material and Methods

5.1 Introduction 27

5.2 Induction of dystonic attacks and severity score of dystonia 27-28

5.3 Slice preparation 28

5.4 Electrophysiological Recording 29-30

5.5 Drug Application 30


v Results

6.1 Synaptic plasticity and network excitability after dystonic attacks and in symptom-free
intervals 32

6.2 Long-term potentiation in corticostriatal slices in young dystonic hamsters 32-33

6.3 Input-output relationships of afferent stimulation in young dystonic hamsters 33-34

6.4 Paired-pulse facilitation before and after long-term synaptic changes 34

6.5 Synaptic plasticity and network excitability in dystonic hamsters in remission state 34-35

6.6 Long-term potentiation in corticostriatal slices in old dystonic hamsters in remission state
35-36
6.7 Input-output relationships of afferent stimulation in old dystonic hamsters in remission
state 36

6.8 Paired-pulse facilitation before and after long-term synaptic changes in old dystonic
hamsters in the remission state 36-37

6.9 Role of NMDA-receptors in dystonia associated synaptic plasticity changes 37

6.10 Blockade of NMDA receptors 37

6.11 Role of NMDA-receptor subunits 37-38

6.12 The role of NMDA receptor subunits in the induction of LTP in normal corticostriatal
slices from healthy animals 38-39


vi Discussion

7.1 Long term plasticity in young dystonic mutants 57-59

7.2 Functioanl changes during maturation 59-60

sz 7.3 The role of NMDA receptors in LTP expression in dt mutants 60-62

7.4 The role of NMDA receptor subunits in long-term plasticity in corticostriatal synapses
sz of dt mutants and normal hamsters 62-63

References

8.1 List of References 65-87




















vii

Abbreviations

1. AMPA α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
2. CA1 Cornu ammonis region 1
3. CaMKII Calcium Calmodulin dependent kinase two
4. GABA γ-aminobutyric acid
5. GluR1 Glutamate receptor 1
6. GPe Globus pallidus external segment
7. GPi Globus pallidus internal segment
8. HFS High frequency stimulation
9. D-AP5 D-2-amino-5-phosphonopentanoate
10. D/NS Dystonic non stimulated
11. D/S Dystonic stimulated
12. D1 receptor Dopamine 1 receptors
13. D2 receptor Dopamine 2 receptors
sz 14. dt Genetically dystonic hamster
15. LFS Low frequency stimulation
16. LTP Long- term potentiation
17. LTD Long-term depression
18. NBQX 2,3-dioxo-6-nitro-7-sulfamoylbnzo(f)quinoxaline
19. ND/NS Non dystonic non stimulated
20. ND/S Non dystonic stimulated
21. NMDA N-methyl-D-aspartate
22. NMDAR N-methyl-D-aspartate receptor
23. NR2A N-metor 2 subtype A
24. NVP-AAAO77 (R)- [S)-1-(4-bromo-phenyl)-ethylamino]-(2,3-dioxo-
1,2,3,4-tetrahydroquinoxalin-5-yl)-methyl-phosphonic
acid
25. PKA Protein kinase A
26. PKC Protein kinase C
27. 38 MAPK 38 mitogen-activated protein kinase P P
28. Rap Ras related protein
viii 29. Ras Guanine nucleotide binding protein
30. RO 25-6981 (αR, ßS)-α-(4-hydroxyphenyl)-ß-methyl-4-
(phenylmethyl)-1- piperidinepropanol
31. SCH-23390 R (+) -7-chloro-8-hydroxy-3-methyl-1-phenyl-1,2,3,4,5
-tetrahydro-1H-3-benzazepine hydrochloride
32. Ser Serine
33. SNr Substantia nigra par reticulata
34. STN Subthalamic nucleus


























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