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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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.
The authors declare no competing financial interests.
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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