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

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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References

  1. LeDoux, J.E. Emotion circuits in the brain. Annu. Rev. Neurosci. 23, 155–184 (2000).

    Article  CAS  Google Scholar 

  2. Maren, S. & Quirk, G.J. Neuronal signalling of fear memory. Nat. Rev. Neurosci. 5, 844–852 (2004).

    Article  CAS  Google Scholar 

  3. Rumpel, S., LeDoux, J.E., Zador, A. & Malinow, R. Postsynaptic receptor trafficking underlying a form of associative learning. Science 308, 83–88 (2005).

    Article  CAS  Google Scholar 

  4. Weisskopf, M.G., Bauer, E.P. & LeDoux, J.E. L-type voltage-gated calcium channels mediate NMDA-independent associative long-term potentiation at thalamic input synapses to the amygdala. J. Neurosci. 19, 10512–10519 (1999).

    Article  CAS  Google Scholar 

  5. Bissière, S., Humeau, Y. & Lüthi, A. Dopamine gates LTP induction in lateral amygdala by suppressing feedforward inhibition. Nat. Neurosci. 6, 587–592 (2003).

    Article  Google Scholar 

  6. Humeau, Y. et al. Dendritic spine heterogeneity determines afferent-specific Hebbian plasticity in the amygdala. Neuron 45, 119–131 (2005).

    Article  CAS  Google Scholar 

  7. McKernan, M.G. & Shinnick-Gallagher, P. Fear conditioning induces a lasting potentiation of synaptic currents in vitro. Nature 390, 607–611 (1997).

    Article  CAS  Google Scholar 

  8. Humeau, Y., Shaban, H., Bissière, S. & Lüthi, A. Presynaptic induction of heterosynaptic associative plasticity in the mammalian brain. Nature 426, 841–845 (2003).

    Article  CAS  Google Scholar 

  9. Sugita, S., Tanaka, E. & North, R.A. Membrane properties and synaptic potentials of three types of neurones in rat lateral amygdala. J. Physiol. (Lond.) 460, 705–718 (1993).

    Article  CAS  Google Scholar 

  10. Li, X.F., Armony, J.L. & LeDoux, J.E. GABAA and GABAB receptors differentially regulate synaptic transmission in the auditory thalamo-amygdala pathway: an in vivo microiontophoretic study and a model. Synapse 24, 115–124 (1996).

    Article  CAS  Google Scholar 

  11. Lang, E.J. & Paré, D. Synaptic and synaptically activated intrinsic conductances underlie inhibitory potentials in cat lateral amygdaloid projection neurons in vivo. J. Neurophysiol. 77, 353–363 (1997).

    Article  CAS  Google Scholar 

  12. Kullmann, D.M. et al. Presynaptic, extrasynaptic and axonal GABAA receptors in the CNS: where and why? Prog. Biophys. Mol. Biol. 87, 33–46 (2005).

    Article  CAS  Google Scholar 

  13. Thompson, S.M., Capogna, M. & Scanziani, M. Presynaptic inhibition in the hippocampus. Trends Neurosci. 16, 222–227 (1993).

    Article  CAS  Google Scholar 

  14. Cryan, J.F. & Kaupmann, K. Don't worry 'B' happy!: a role for GABA(B) receptors in anxiety and depression. Trends Pharmacol. Sci. 26, 36–43 (2005).

    Article  CAS  Google Scholar 

  15. Isaacson, J.S., Solis, J.M. & Nicoll, R.A. Local and diffuse synaptic actions of GABA in the hippocampus. Neuron 10, 165–175 (1993).

    Article  CAS  Google Scholar 

  16. Dittman, J.S. & Regehr, W.G. Mechanism and kinetics of heterosynaptic depression at a cerebellar synapse. J. Neurosci. 17, 9048–9059 (1997).

    Article  CAS  Google Scholar 

  17. Porter, J.T. & Nieves, D. Presynaptic GABAB receptors modulate thalamic excitation of inhibitory and excitatory neurons in the mouse barrel cortex. J. Neurophysiol. 92, 2762–2770 (2004).

    Article  CAS  Google Scholar 

  18. Asprodini, E.K., Rainnie, D.G. & Shinnick-Gallagher, P. Epileptogenesis reduces the sensitivity of presynaptic gamma-aminobutyric acidB receptors on glutamatergic afferents in the amygdala. J. Pharmacol. Exp. Ther. 262, 1011–1021 (1992).

    CAS  PubMed  Google Scholar 

  19. Yamada, J., Saitow, F., Satake, S., Kiyohara, T. & Konishi, S. GABA(B) receptor-mediated presynaptic inhibition of glutamatergic and GABA-ergic transmission in the basolateral amygdala. Neuropharmacology 38, 1743–1753 (1999).

    Article  CAS  Google Scholar 

  20. Bettler, B., Kaupmann, K., Mosbacher, J. & Gassmann, M. Molecular structure and physiological functions of GABA(B) receptors. Physiol. Rev. 84, 835–867 (2004).

    Article  CAS  Google Scholar 

  21. Fritschy, J.M. et al. GABAB-receptor splice variants GB1a and GB1b in rat brain: developmental regulation, cellular distribution and extrasynaptic localization. Eur. J. Neurosci. 11, 761–768 (1999).

    Article  CAS  Google Scholar 

  22. McDonald, A.J., Mascagni, F. & Muller, J.F. Immunocytochemical localization of GABABR1 receptor subunits in the basolateral amygdala. Brain Res. 1018, 147–158 (2004).

    Article  CAS  Google Scholar 

  23. Lüscher, C., Jan, L.Y., Stoffel, M., Malenka, R.C. & Nicoll, R.A. G protein-coupled inwardly rectifying K+ channels (GIRKs) mediate postsynaptic but not presynaptic transmitter actions in hippocampal neurons. Neuron 19, 687–695 (1997).

    Article  Google Scholar 

  24. Huang, Y.Y. & Kandel, E.R. Postsynaptic induction and PKA-dependent expression of LTP in the lateral amygdala. Neuron 21, 169–178 (1998).

    Article  CAS  Google Scholar 

  25. Szinyei, C., Heinbockel, T., Montagne, J. & Pape, H.C. Putative cortical and thalamic inputs elicit convergent excitation in a population of GABAergic interneurons of the lateral amygdala. J. Neurosci. 20, 8909–8915 (2000).

    Article  CAS  Google Scholar 

  26. Sugita, S. & North, R.A. Opioid actions on neurons of rat lateral amygdala in vitro. Brain Res. 612, 151–155 (1993).

    Article  CAS  Google Scholar 

  27. Billinton, A., Upton, N. & Bowery, N.G. GABA(B) receptor isoforms GBR1a and GBR1b, appear to be associated with pre- and postsynaptic elements respectively in rat and human cerebellum. Br. J. Pharmacol. 126, 1387–1392 (1999).

    Article  CAS  Google Scholar 

  28. Benke, D., Honer, M., Michel, C., Bettler, B. & Mohler, H. Gamma-aminobutyric acid type B receptor splice variant proteins GBR1a and GBR1b are both associated with GBR2 in situ and display differential regional and subcellular distribution. J. Biol. Chem. 274, 27323–27330 (1999).

    Article  CAS  Google Scholar 

  29. Vigot, R. et al. Different compartmentalization and distinct functions of GABAB receptor variants. Neuron 50, 589–601 (2006).

    Article  CAS  Google Scholar 

  30. Perez-Garci, E., Gassmann, M., Bettler, B. & Larkum, M.E. The GABA(B1b) isoform mediates long-lasting inhibition of dendritic Ca2+ spikes in layer 5 somatosensory pyramidal neurons. Neuron 50, 603–616 (2006).

    Article  CAS  Google Scholar 

  31. Davies, C.H., Starkey, S.J., Pozza, M.F. & Collingridge, G.L. GABA autoreceptors regulate the induction of LTP. Nature 349, 609–611 (1991).

    Article  CAS  Google Scholar 

  32. Kulik, A. et al. Distinct localization of GABAB receptors relative to synaptic sites in the rat cerebellum and ventrobasal thalamus. Eur. J. Neurosci. 15, 291–307 (2002).

    Article  Google Scholar 

  33. Jarrell, T.W., Gentile, C.G., Romanski, L.M., McCabe, P.M. & Schneiderman, N. Involvement of cortical and thalamic auditory regions in retention of differential bradycardia conditioning to acoustic conditioned stimuli in rabbits. Brain Res. 412, 285–294 (1987).

    Article  CAS  Google Scholar 

  34. Armony, J.L., Servan-Schreiber, D., Romanski, L.M., Cohen, J.D. & LeDoux, J.E. Stimulus generalization of fear responses: effects of auditory cortex lesions in a computational model and in rats. Cereb. Cortex 7, 157–165 (1997).

    Article  CAS  Google Scholar 

  35. Laxmi, T.R., Stork, O. & Pape, H.C. Generalisation of conditioned fear and its behavioural expression in mice. Behav. Brain Res. 145, 89–98 (2003).

    Article  Google Scholar 

  36. Baldi, E., Lorenzini, C.A. & Bucherelli, C. Footshock intensity and generalization in contextual and auditory-cued fear conditioning in the rat. Neurobiol. Learn. Mem. 81, 162–166 (2004).

    Article  Google Scholar 

  37. Xia, Z. & Storm, D.R. The role of calmodulin as a signal integrator for synaptic plasticity. Nat. Rev. Neurosci. 6, 267–276 (2005).

    Article  CAS  Google Scholar 

  38. Nicoll, R.A. & Malenka, R.C. Contrasting properties of two forms of long-term potentiation in the hippocampus. Nature 377, 115–118 (1995).

    Article  CAS  Google Scholar 

  39. Lauri, S.E. et al. A critical role of a facilitatory presynaptic kainate receptor in mossy fiber LTP. Neuron 32, 697–709 (2001).

    Article  CAS  Google Scholar 

  40. Schmitz, D., Mellor, J., Breustedt, J. & Nicoll, R.A. Presynaptic kainate receptors impart an associative property to hippocampal mossy fiber long-term potentiation. Nat. Neurosci. 6, 1058–1063 (2003).

    Article  CAS  Google Scholar 

  41. Thompson, R.F. The role of the cerebral cortex in stimulus generalization. J. Comp. Physiol. Psychol. 55, 279–287 (1962).

    Article  CAS  Google Scholar 

  42. Weinberger, N.M. Specific long-term memory traces in primary auditory cortex. Nat. Rev. Neurosci. 5, 279–290 (2004).

    Article  CAS  Google Scholar 

  43. Collins, D.R. & Paré, D. Differential fear conditioning induces reciprocal changes in the sensory responses of lateral amygdala neurons to the CS(+) and CS(-). Learn. Mem. 7, 97–103 (2000).

    Article  CAS  Google Scholar 

  44. Mahanty, N.K. & Sah, P. Calcium-permeable AMPA receptors mediate long-term potentiation in interneurons in the amygdala. Nature 394, 683–687 (1998).

    Article  CAS  Google Scholar 

  45. Marsicano, G. et al. The endogenous cannabinoid system controls extinction of aversive memories. Nature 418, 530–534 (2002).

    Article  CAS  Google Scholar 

  46. Bauer, E.P. & LeDoux, J.E. Heterosynaptic long-term potentiation of inhibitory interneurons in the lateral amygdala. J. Neurosci. 24, 9507–9512 (2004).

    Article  CAS  Google Scholar 

  47. Zhu, P.J. & Lovinger, D.M. Retrograde endocannabinoid signaling in a postsynaptic neuron/synaptic bouton preparation from basolateral amygdala. J. Neurosci. 25, 6199–6207 (2005).

    Article  CAS  Google Scholar 

  48. Pelletier, J.G. & Paré, D. Role of amygdala oscillations in the consolidation of emotional memories. Biol. Psychiatry 55, 559–562 (2004).

    Article  Google Scholar 

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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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Correspondence to Andreas Lüthi.

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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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