Impaired representation of space in the hippocampus of GluR-A knockout mice [Elektronische Ressource] / presented by Evgeny Resnik

Evgeny Epifanovsky*†

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• Gesundheit

Informations

• Publié par: ruprecht-karls-universitat_heidelberg
• Publié le: 01 janvier 2008
• Nombre de lectures: 28
• Langue: Deutsch
• Poids de l'ouvrage: 2 Mo

Extrait

Dissertation
submitted to the
Combined Faculties for the Natural Science and for Mathematics
of the Ruperto-Carola University of Heidelberg, Germany
for the degree of
Doctor of Natural Science


















presented by
Master in applied mathematics and physics: Evgeny Resnik
born in: Enakiewo, Ukraine

Oral examination: 12.12.2007




Impaired representation of space in the hippocampus of
GluR-A knockout mice



















Referees: Prof. Dr. Bert Sakmann
Prof. Dr. Heinz Horner
Co-adviser: Dr. Mayank Mehta (Brown University, USA)


2SUMMARY

Um die Rolle der AMPAR vermittelten synaptischen Transmission bei der ortsabhängigen
Aktivität hippokampaler CA1 Pyramidalzellen zu untersuchen, haben wir
Aufzeichnungstechniken mit Mehrfach - Tetroden an sich freilaufenden Mäusen mit
defektem GluR-A-Gen vorgenommen. Wir haben gefunden, dass bei den GluR-A
Knockout Mäusen die ortsabhängige Aktivität der analysierten Nervenzellen beeinträchtigt
war. Die Pyramidenzellen bildeten Aktivitätsfelder aus, die in im Vergleich zu
Wildtypgeschwister Mäusen in GluR-A defizienten Mäusen signifikant größer (160-
200%), weniger selektiv im Allgemeinen (73%), bezüglich der Richtung (39%) weniger
stabil (53%) waren und weniger Information zur Position des Tieres trugen (47%). Trotz
der beobachteten positiven Korrelation zwischen den Eigenschaften der Aktivitätsfelder
und dem Grad der kognitiven Anforderung der drei hier untersuchten Verhaltensaufgaben,
waren die räumlichen Aktivitätsdefizite der GluR-A Knockout Mäuse konsistent und
unabhängig von deren Komplexität der Verhaltensaufgabe. Die Frequenz des
hippokampalen Theta-Rhythmus war durch den Verlust des funktionellen GluR-A Gens
leicht herabsetzt. Das relative Spike-Timing der Pyramidalzellen in Bezug auf den Theta-
Rhythmus war jedoch normal. Diese Ergebnisse unterstreichen die Funktion der AMPA
Rezeptoren mit GluR-A Untereinheit für eine korrekte, interne räumliche Repräsentation
in der CA1-Region des Hippokampus, was wiederum für ein effektives Arbeitsgedächtnis
wichtig zu seien scheint.







To investigate the role of AMPAR-mediated synaptic transmission in the place-
specific firing of the hippocampal CA1 pyramidal cells, we have applied multiple tetrode
recording techniques in freely behaving mice with a complete knockout of the GluR-A
gene. We have found that place-specific activity of the neurons was significantly impaired
in the GluR-A KO mice. The pyramidal cells in GluR-A KO mice formed firing (place)
fields, that were: significantly larger (160-200%), less location selective (73%), less
direction selective (39%), less stable (53%) and carried less information about the animal’s
position (47%) than those cells studied in wild-type mice. Despite the observed positive
correlation between the firing field’s properties and the degree of cognitive demands of
three employed behavioral paradigms, the spatial firing defects were consistent across the
paradigms independent from their complexity. We have also found that deletion of the
GluR-A gene slightly reduced (5%) the frequency of the hippocampal theta rhythm, but
did not affect relative timing of the pyramidal cell spikes in respect to the theta rhythm.
These results demonstrate that GluR-A-containing AMPA receptors are necessary for the
normal representation of space in the CA1 region of the hippocampus, which might be
necessary for the flexible working memory system.



3ACKNOWLEDGEMENTS

I want to take this moment to thank a number of people. First of all, my wife Olga,
for her faith in me and her patience in dealing with me in these trying times; my 2-months
old son Phillip, who has motivated me to take, finally, the last step and write the thesis; my
parents for unconditional support, which made this easier than it could have been.
I would like to express my gratitude to Prof. Bert Sakmann for launching and further
support of this long-lasting project despite many technical difficulties I had at the
beginning. I am especially grateful to my advisor Dr. Mayank Mehta (Brown University,
USA) for introducing me to a nice technique of extracellular recording in awake behaving
mice, and for sharing his great experience in the analysis of experimental data.
I would like to thank Dr. Tansu Celikel, for the permanent support during all the time
I worked in the Department of Cell Physiology, as well as for never sparing his time when
I asked him to discuss the data or to read critically different parts of this dissertation. A
special thanks to him for the collaboration in developing a new microdrive for chronic
extracellular recording, after almost 1.5 years of unsuccessful efforts to record units with
the original one.
I would like to thank also Prof. Peter Seeburg, Dr. Rolf Sprengel and Verena Bosch
from the Department of Molecular Neurobiology who provided me with these nice dumb
GluR-A knockout mice.
I am grateful to all members of the local Russian community: Prof. Dr. Nail
Burnashev, Dr. Andrey Rozov, Dr. Alexandr Kolleker, Dr. Alexey Ponomarenko and Dr.
Tatjana Korotkova, who helped me a lot with their experience and knowledge in both
scientific and everyday life.
Thanks to all other members of the lab for creating such a friendly atmosphere in
which it was a real pleasure to work.
The work presented in this thesis was supported by the Max Plank Society.









4CONTENTS

1. INTRODUCTION -------------------------------------------------------------------------------------- 8
1.1. THE HIPPOCAMPUS --------------------------------------------------------------------------------- 8
1.1.1. Gross anatomy----------------------------------------------------------------------------------- 8
1.1.2. Cell types ----------------------------------------------------------------------------------------- 9
1.1.3. Connections with other areas ----------------------------------------------------------------- 9
1.1.4. Internal circuitry ------------------------------------------------------------------------------ 10
1.1.5. Synaptic plasticity and memory ------------------------------------------------------------- 11
1.1.6. NMDA receptor and its role in synaptic plasticity and memory------------------------ 13
1.1.7. AMPA receptor and its role in synaptic plasticity and memory ------------------------ 15
1.1.8. Electrophysiological and behavioral characterization of GluR-A knockout mice --- 17
1.2. RATE CODING: HIPPOCAMPAL PLACE CELLS-------------------------------------------------- 19
1.2.1. Evidence supporting that place cells are part of a cognitive map---------------------- 20
1.2.2. Evidence challenging the cognitive map theory ------------------------------------------ 22
1.2.3. Place cells and spatial learning------------------------------------------------------------- 24
1.2.4. Place cells and synaptic plasticity ---------------------------------------------------------- 25
1.2.5. Cells with spatial correlates outside the rodent hippocampus-------------------------- 30
1.3. THETA OSCILLATION IN THE HIPPOCAMPUS -------------------------------------------------- 32
1.3.1. Electrophysiological characterization of theta oscillation ------------------------------ 33
1.3.2. Rhythm generating mechanisms ------------------------------------------------------------ 33
1.3.3. Behavioral correlates of theta oscillation ------------------------------------------------- 34
1.3.4. Theta oscillation and cognitive processing--------- 35
1.3.5. Theta oscillation and synaptic plasticity--------------------------------------------------- 36
1.3.6. Theta phase precession and phase coding----------------------- 36
1.3.7. Other hippocampal rhythms ----------------------------------------------------------------- 37
1.4. AIM OF THE THESIS------------------------------------------------------------------------------- 39
2. METHODS --------------------------------------------------------------------------------------------- 40
2.1. SUBJECTS ------------------------------------------------------------------------------------------ 40
2.2. SURGICAL IMPLANTATION OF MICRODRIVE -------------------------------------------------- 40
2.3. BEHAVIORAL TRAINING AND TETRODES ADJUSTING ---------------------------------------- 41
2.4. ELECTROPHYSIOLOGICAL RECORDING -------------------------------------------------------- 43
2.5. DATA ANALYSIS ---------------------------------------------------------------------------------- 44
2.5.1. Identification of recorded cells-------------------------------------------------------------- 44
2.5.2. Quantification of basic firing properties of cells ----------------------------------------- 45
52.5.3. Quantification of spat