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Gabab Receptor-Mediated Modulation of Synaptic GABAB RECEPTOR-MEDIATED MODULATION OF SYNAPTIC PLASTICITY IN THE LATERAL AMYG DALA Inaugurald issertation zu r Erlangung der Würde eines Doktors der Philosophie vorgele gt der Philosophisch-Naturwissen schaftlichen Fakultät der Universität Basel vo n Hamdy Shaban aus Alexandria, Aegypten Genehmigt von der Philosophisch-Naturwissenschaftlichen Fakultät auf Antrag von Prof. Dr. Andreas Lüthi , Prof. Dr.Bernhard Bettler Basel, den 24.5.2005 Dekan Prof. Dr. Hans-Jakob Wirz Table of contents 3 TABLE OF CONTENTS 1. Summary………………...……………………………………………….…. 5 2. Introduction ……………………..……………………………………….… 7 2.1. Fear emotion and memory formation……………………………...... 7 2.1.1. Early thoughts about emotion……………….………..………….… 7 2.1.2. Fear conditioning and the amygdala………………………….….… 8 2.1.3. The amygaloid complex: structure and connectivity………………. 11 2.1.4. Fear conditioning and synaptic plasticity……………..…………… 13 2.2. Synaptic plasticity…………………………………..………………… 16 2.2.1. Short-term plasticity……………………………………...………… 16 2.2.2. Long-term plasticity………………………………………….….…. 18 2.2.3. Presynaptic long-term potentiation: hippocampal mossy fiber LTP. 19 2.2.4. Postsynaptic signal cascade of LTP induction and expression…….. 20 2.2.5. The Hebb rule of synaptic plasticity………………………….……. 21 2.2.6. LTD, a different form of synaptic plasticity………………………. 22 2.2.7. Metaplasticity and the switch between LTP and LTD………..……. 23 2.3. Inhibition in the amygdala …………………………………….…….. 25 2.3.1. Interneurons in the amygdala ……………………………..……….. 25 2.3.2. Ionotropic GABAA receptors ……………………………..……….. 27 2.3.3. Metabotropic GABAB receptors ………………………..……..….. 28 2.3.4. Molecular structure of GABAB receptors…………………………. 29 2.3.5. GABAB receptor-mediated signaling……………………………… 31 2.3.6. GABAB receptor-mediated inhibition in the LA……………..……. 33 2.3.7. GABAergic modulation of synaptic plasticity in the LA….……… 35 2.3.8. The loss of inhibition and anxiety…………………………….……. 37 3. The aim of the study …………………..………………….…………....… 38 4. Materials and methods ………………………………….………….…… 39 4.1. Mouse brain slice preparation……………………………………….….… 39 4.2. Electrophysiology………………………………………………………… 39 4.3. Data analysis…………………………………………..…………….....… 41 4.4. Behavior experiments……………………………………..................…… 42 4.5. Drugs……………………………………………………………………… 43 5. Results…………………………………………..…………………………… 44 5.1. Presynaptic induction of heterosynaptic associative plasticity in the mammalian brain…………………………………………….…….….… 44 5.2. GABAB(1a) heteroreceptors modulate associative properties of presynaptic LTP and learning………………………………………...…57 5.2.1. Summary………………….……………….………………….…… 57 5.2.2. Introduction…………………………………...…………………… 58 5.2.3. Methods……………………………………………………………..59 5.2.4. Results…………………………..…………………….……….…… 61 5.2.5. Discussion…………….……………………………………….…… 74 -3- Table of contents 4 5.3. Postsynaptic GABAB(1b) receptors modulate the induction of homosynaptic LTP at thalamic afferents………….……..………..... 77 5.3.1. Summary………………………………………..…………………. 77 5.3.2. Introduction……………………………………...………………… 78 5.3.3. Methods………..………………………………………..………… 79 5.3.4. Results…………..………………………………………..………… 81 5.3.5. Discussion………………………………………….…………….… 93 5.4. Redistribution of GABAB(1) Protein and Atypical GABAB Responses in GABAB(2)-Deficient Mice …………..………………………..………. 98 5.4.1. Summary……………………………………….……………..…… 98 5.4.2. Introduction……………………...…………………….…………… 99 5.4.3. Methods………………..……………………………………….…. 100 5.4.4. Results…………………..……………………………………….… 105 5.4.5. Discussion…………………….……………………………….…… 124 6. Discussion………………………………..…………….…………………… 128 6.1. Pre- and postsynaptic GABABR-mediated inhibition in the LA…... 128 6.2. GABAB heteroreceptor-mediated inhibition at thalamic and cortical afferents is impaired in GABAB(1a) -/- mice ………………….……… 132 6.3. GABAB-mediated modulation of homosynaptic and heterosynaptic LTP at cortical afferents ………………..………………………….. 134 6.4. Homosynaptic LTP at thalamic afferents is postsynaptically induced………………………….………………………..……….…… 137 6.5. Intrinsic properties of GABAB receptors …………...……………… 139 6.6. Relevance of the GABABR-modulation of synaptic plasticity in LA in anxiety treatment ………………………………….……………… 140 6.7. Outlook and future experiments …………………………..…...…… 144 7. List of abbreviations……………………………………..….………… 145 8. References……………………………..……………………………………. 147 9. Acknowledgements ………………………..…………………………….. 172 10. Curriculum Vitae ….…………………………...………………………… 173 -4- Summary 5 1. SUMMARY Fear conditioning, one of the most powerful and widely used methods to investigate the mechanisms of associative learning in animals, involves the pairing of an aversive stimulus such as a foot-shock (the unconditioned stimulus; US) with a neutral stimulus such as a tone (the conditioned stimulus; CS). The tone acquires aversive properties and, on subsequent exposure, will elicit a fear response. Behavioral and in vivo electrophysiological experiments indicate that NMDA receptor-mediated long-term potentiation (LTP) in the lateral amygdala (LA), a key structure for emotional learning, underlies the acquisition of Pavlovian fear conditioning. Neuronal activity in the LA is tightly controlled by local inhibitory interneurons. Interneurons exert their inhibitory effect by releasing the neurotransmitter GABA acting on ionotropic GABAA and metabotropic GABAB receptors. There is accumulating evidence suggesting a role for GABAA and GABAB receptors in regulating amygdala- dependent fear and anxiety behavior. However, whereas the role of GABAA receptors for postsynaptic integration and gating of LTP induction is well documented, nothing is known about the role of GABAB receptors in the LA. GABABRs are G-protein-coupled receptors that are localized both pre- and + postsynaptically. Postsynaptic GABABRs are coupled to inwardly rectifying K channels. 2+ Presynaptic GABABRs inhibit neurotransmitter release by decreasing Ca influx at both GABAergic terminals and glutamatergic terminals. Functional GABAB receptors are generally thought to be heterodimers containing GABAB(1) and GABAB(2) subunits. The GABAB(1) subunit exists in two differentially expressed isoforms, GABAB(1a) and GABAB(1b), differing by the presence of two N-terminal “sushi” domains in the GABAB(1a) isoform. In the main study of the present thesis, using a combined electrophysiological and genetic approach in mice, I found that presynaptic GABAB heteroreceptors on glutamatergic cortical afferents are predominantly comprised of GABAB(1a) subunits, and critically determine associative properties of presynaptic cortical LTP. In the absence of functional presynaptic GABAB heteroreceptors, an NMDA receptor-independent, non-associative -5- Summary 6 form of presynaptic LTP is unmasked. Strikingly, the loss of associativity of cortico- amygdala LTP is accompanied by a generalization of conditioned fear at the behavioral level. This indicates that the specificity of information processing in the LA can be set by activity-dependent presynaptic inhibition mediated by specific GABAB receptors. In contrast to synaptic plasticity at cortico-amygdala afferents, I found that at thalamic afferents, GABAB receptors facilitate LTP induction by a postsynaptic mechanism. Moreover, this effect could be attributed to GABAB(1b) containing receptors. Thus, in the LA specific subtypes of pre- and postsynaptic GABAB receptors control induction pre- or postsynaptic LTP in an afferent-specific manner. Taken together, the present findings indicate that GABAB receptors are playing a key role in controlling associative plasticity in the LA, and suggest that GABAB receptors could be a pharmacological target for treatment of psychiatric conditions like anxiety and post traumatic stress disorder. -6- Introduction 7 2. INTRODUCTION 2. Overview In this introduction, I will go through the historical development and the early hypothesis about the formation of emotional memory. Later, I will outline the anatomical features of one of the key structures in fear memory formation, namely the amygdaloid nucleus, and its connectivity to other brain areas. Then I will discuss the different cellular mechanisms of synaptic plasticity implicated in fear memory formation. Finally, I will elucidate the important role of inhibition in the lateral amygdala. 2.1. Fear emotion and memory formation Our memories are our identity. All information is stored in the brain by an unknown encoding mechanism. However, not all information is stored in the same intensity. The reason why some memories remain in our mind forever and others not, is embedded in the emotional information accompanying this memory formation. Whether it is a pleasant emotion or an aversive one, both reinforce memory formation in the brain. Here, I will focus only on the formation of fear memory on the brain. Fear associative learning in mammalian is organized into separate anatomically defined functional systems. The amygdala serves as the neuroanatomical hub of fear memory formation. Pathways that convey information about signals for biologically important events arrive at these hubs by circuitry that depends on stimulus modality and complexity. Within the amygdala, neural plasticity occurs because of convergence of these stimuli and the biologically important information they predict. This neural plasticity is the physical basis of associative memory formation 2.1.1. Early thoughts about emotion Charles Darwin, in 1872, was the first who described that the expression of emotions in humans and animals is similar (Darwin 1872/1965). By comparing and analysing several -7- Introduction 8 sketches
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