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Generalization of amygdala LTP and conditioned fear in the absence of presynaptic inhibition

Nature Neuroscience volume 9, pages 1028–1035 (2006)Cite this article

Abstract

Pavlovian fear conditioning, a simple form of associative learning, is thought to involve the induction of associative, NMDA receptor–dependent long-term potentiation (LTP) in the lateral amygdala. Using a combined genetic and electrophysiological approach, we show here that lack of a specific GABAB receptor subtype, GABAB(1a,2), unmasks a nonassociative, NMDA receptor–independent form of presynaptic LTP at cortico-amygdala afferents. Moreover, the level of presynaptic GABAB(1a,2) receptor activation, and hence the balance between associative and nonassociative forms of LTP, can be dynamically modulated by local inhibitory activity. At the behavioral level, genetic loss of GABAB(1a) results in a generalization of conditioned fear to nonconditioned stimuli. Our findings indicate that presynaptic inhibition through GABAB(1a,2) receptors serves as an activity-dependent constraint on the induction of homosynaptic plasticity, which may be important to prevent the generalization of conditioned fear.

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Figure 1: GABAB receptor blockade enables the induction of homosynaptic, nonassociative LTP at cortical afferents to the lateral amygdala.
Figure 2: Induction of homosynaptic LTP at cortical afferents is independent of NMDA receptor activation and postsynaptic Ca2+.
Figure 3: Synaptic activation of presynaptic GABAB receptors.
Figure 4: Neuromodulator-mediated suppression of GABA release gates homosynaptic LTP induction.
Figure 5: GABAB(1a) receptors are the predominant presynaptic heteroreceptors at cortical afferents.
Figure 6: Ultrastructual localization of GABAB(1a) and GABAB(1b) in the lateral amygdala.
Figure 7: GABAB(1a)-deficient mice exhibit facilitated homosynaptic LTP induction at cortical afferents.
Figure 8: Generalization of conditioned fear in GABAB(1a)−/− mice.

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Acknowledgements

We thank J. Cryan, B. Gähwiler, K. Vogt and all members of the Lüthi lab for helpful discussions and comments on the manuscript. This work was supported by the Swiss Science Foundation, the Centre National de la Recherche Scientifique (CNRS), and the Novartis Research Foundation.

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Authors and Affiliations

  1. Friedrich Miescher Institute for Biomedical Research, Basel, CH-4058, Switzerland

    Hamdy Shaban, Yann Humeau, Cyril Herry, Guillaume Cassasus, Stephane Ciocchi & Andreas Lüthi

  2. Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7168, Strasbourg, F-67084, France

    Yann Humeau

  3. Division of Cerebral Structure, National Institute for Physiological Sciences, Myodaiji, Okazaki 444-8585, CREST, Japan Science and Technology Corporation, Kawaguchi, Japan

    Ryuichi Shigemoto

  4. Department of Clinical-Biological Sciences, Pharmazentrum, University of Basel, Basel, CH-4056, Switzerland

    Samuel Barbieri & Bernhard Bettler

  5. Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, CH-4002, Switzerland

    Herman van der Putten & Klemens Kaupmann

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Supplementary information

Supplementary Fig. 1

Baclofen-induced presynaptic inhibition of monosynaptic IPSCs is not affected in GABAB(1a)- or GABAB(1b)-deficient mice. (PDF 11 kb)

Supplementary Fig. 2

Synaptic activation of presynaptic GABAB receptors is lost in GABAB(1a)−/− mice. (PDF 17 kb)

Supplementary Fig. 3

GABAB receptor blockade facilitates postsynaptic induction of NMDA receptor-dependent LTP at thalamic afferents to the lateral amygdala. (PDF 86 kb)

Supplementary Fig. 4

Absence of conditioned fear in GABAB(1b)−/− mice. (PDF 16 kb)

Supplementary Fig. 5

Increasing stimulation frequency during LTP induction (45 stimuli) in the absence of CGP55845A does not induce significant homosynaptic non-associative LTP at cortical afferents. (PDF 11 kb)

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Shaban, H., Humeau, Y., Herry, C. et al. Generalization of amygdala LTP and conditioned fear in the absence of presynaptic inhibition. Nat Neurosci 9, 1028–1035 (2006). https://doi.org/10.1038/nn1732

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