Role of the cannabinoid receptor type 1 (CB1) in synaptic plasticity, memory and emotionality [Elektronische Ressource] / vorgelegt von Wolfgang Jacob

Wolfgang Jacob

Sujets

• Gesundheit

Informations

• Publié par: ludwig-maximilians-universitat_munchen
• Publié le: 01 janvier 2007
• Nombre de lectures: 8
• Langue: English
• Poids de l'ouvrage: 2 Mo

Extrait

Dissertation zur Erlangung des Doktorgrades der Naturwissenschaften
(Doctor rerum naturalium)
an der Fakultät für Biologie
der Ludwig-Maximilians-Universität München


Role of the Cannabinoid Receptor
Type 1 (CB1) in Synaptic Plasticity,
Memory and Emotionality


Vorgelegt von

Wolfgang Jacob

aus Lich















München, 28. März 2007

































1. Gutachter: Prof. Dr. Mark Hübener
2.ter: PD Dr. Lutz Wiegrebe
Promotionsbetreuer: Dr. Carsten T. Wotjak
Tag der mündlichen Prüfung: 26.7.2007




2






“If a man will begin with certainties, he shall end in doubts; but if he
will be content to begin with doubts he shall end in certainties.”

Francis Bacon








3Table of contents
Abbreviations.............................................................................................................. 9
Abstract ..................................................................................................................... 11
1. Introduction........................................................................................................... 13
1.1 May CB1 be with you! .................................................................................... 13
1.2 Overview of the endocannabinoid system: neuroanatomy of CB1 .......... 13
1.3 CB1 and its signal transduction pathways.................................................. 14
1.4 Endocannabinoids ......................................................................................... 15
1.5 Effects of CB1 activation on transmitter release........................................ 17
1.6CB1 activation on synaptic plasticity......................................... 18
1.7 Aim of the study ............................................................................................. 19
1.7.1 An electrophysiological model for synaptic plasticity in the hippocampus: is
LTP altered in CB1-deficient mice? ................................................................... 21
1.7.2 Behavioural paradigms for the measurement of learning and memory: are
cognitive abilities altered in CB1-deficient mice?............................................... 23
1.7.3 Behavioural models for the measurement of anxiety and emotionality: is
emotionality altered in CB1-deficient mice?....................................................... 25
2. Methods ................................................................................................................. 27
2.1 Animals............................................................................................................ 27
2.1.1 Animal housing.......................................................................................... 27
2.1.2 Generation of CB1 mutant mice................................................................ 27
2.2 Electrophysiology .......................................................................................... 30
2.2.1 Surgery and field recordings..................................................................... 30
2.2.2 Current-response relationships................................................................. 32
2.2.3 Paired-pulse protocols .............................................................................. 32
2.2.4 Induction of long-term potentiation (LTP) ................................................. 33
2.2.5 Hippocampal electroencephalography (EEG) .......................................... 34
2.3 Behavioural Testing....................................................................................... 34
2.3.1 Water maze spatial discrimination task .................................................... 34
2.3.2 Social interaction and olfactory recognition .............................................. 35
2.3.3 Novel object exploration and object recognition ....................................... 36
2.3.5 Contextual fear conditioning ..................................................................... 36
2.3.6 Elevated plus-maze test............................................................................ 38
2.3.7 Light/dark exploration................................................................................ 38
2.3.8 Defensive marble burying ......................................................................... 39
2.3.4 Open field test........................................................................................... 39
2.4 Statistical analysis ......................................................................................... 39
3. Results................................................................................................................... 40
3.1 Electrophysiology .......................................................................................... 40
3.1.1 Current-response relationships................................................................. 40
3.1.2 Paired-pulse facilitation of fEPSP slope ................................................... 40
3.1.3 Paired-pulse inhibition and facilitation of pop-spike.................................. 40
3.1.4 Long-term potentiation (LTP).................................................................... 42
3.1.5 Hippocampal EEG after tail pinch............................................................. 43
4 Table of Contents

3.2 Learning and Memory.................................................................................... 44
3.2.1 Water maze spatial discrimination task .................................................... 44
3.2.2 Social recognition...................................................................................... 45
3.2.3 Object recognition ..................................................................................... 46
3.2.4 Contextual fear conditioning ..................................................................... 47
3.3 Emotionality and Anxiety .............................................................................. 52
3.3.1 Elevated plus-maze................................................................................... 52
3.3.2 Light/dark exploration................................................................................ 55
3.3.3 Defensive marble burying ......................................................................... 56
3.3.4 Social interaction....................................................................................... 56
3.3.5 Novel object exploration............................................................................ 57
3.3.6 Open field test........................................................................................... 57
3.3.7 Open field habituation from day 1 to day 2............................................... 61
4. Discussion............................................................................................................. 64
4.1 Synaptic transmission and plasticity in CB1-ko mice ............................... 64
4.1.1 Effects of CB1 signalling on basal synaptic transmission......................... 64
4.1.2 f CB1 on short term synaptic plasticity ....................... 65
4.1.3 Effects of CB1 signalling on LTP .............................................................. 67
4.1.4 Pitfalls of LTP in anaesthetised mice........................................................ 69
4.1.5 Brain oscillatory activity influenced by CB1 activation.............................. 69
4.2. Memory functions in CB1-ko mice .............................................................. 71
4.2.1 Is there a genuine physiological role of CB1 in memory? ........................ 71
4.3 Modulation of emotionality in CB1-ko mice ................................................ 83
4.3.1 Effects of CB1 signalling on emotionality.................................................. 83
4.4 Pitfalls of the CB1-ko animal model............................................................. 87
4.4.1 Compensatory mechanisms in CB1-ko mice............................................ 88
4.4.2 Genetic background of CB1-ko mice ........................................................ 89
5. Conclusion ............................................................................................................ 90
6. Appendix ............................................................................................................... 91
6.1 Factors for LTP enhancement ...................................................................... 91
6.1.1 Factors for LTP enhancement I: GABA .................................................... 91
6.1.2 Factors for LTP enhancement II: glutamate ............................................. 92
6.1.3 Factors for LTP enhancement III: acetylcholine ....................................... 93
6.1.4 Factors for LTP enhancement IV: cholecystokinin (CCK) ........................ 94
6.1.5 Factors for LTP enhancement V: vanilloid receptor 1 .........