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

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.