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GABA(B) receptor-mediated modulation of synaptic plasticity in the lateral amygdala

Shaban, Hamdy. GABA(B) receptor-mediated modulation of synaptic plasticity in the lateral amygdala. 2005, PhD Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_7349

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Abstract

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 amygdaladependent
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.
Presynaptic GABABRs inhibit neurotransmitter release by decreasing Ca2+ 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
form of presynaptic LTP is unmasked. Strikingly, the loss of associativity of corticoamygdala
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.
Advisors:Lüthi, Andreas
Committee Members:Bettler, Bernhard
Faculties and Departments:09 Associated Institutions > Friedrich Miescher Institut FMI
Item Type:Thesis
Thesis no:7349
Bibsysno:Link to catalogue
Number of Pages:175
Language:English
Identification Number:
Last Modified:30 Jun 2016 10:41
Deposited On:13 Feb 2009 15:21

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