Decreased GABAA-receptor clustering results in enhanced anxiety and a bias for threat cues

Abstract

Patients with panic disorders show a deficit of GABAA receptors in the hippocampus, parahippocampus and orbitofrontal cortex. Synaptic clustering of GABAA receptors in mice heterozygous for the γ2 subunit was reduced, mainly in hippocampus and cerebral cortex. The γ2+/– mice showed enhanced behavioral inhibition toward natural aversive stimuli and heightened responsiveness in trace fear conditioning and ambiguous cue discrimination learning. Implicit and spatial memory as well as long-term potentiation in hippocampus were unchanged. Thus γ2+/– mice represent a model of anxiety characterized by harm avoidance behavior and an explicit memory bias for threat cues, resulting in heightened sensitivity to negative associations. This model implicates GABAA-receptor dysfunction in patients as a causal predisposition to anxiety disorders.

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Figure 1: Region-specific decrease of [3H]flumazenil binding and loss of GABAA-receptor clusters in γ2+/– mice.
Figure 2: Single-channel properties of GABAA receptors and long-term potentiation in γ2+/– mice.
Figure 3: Behavioral responses to natural aversive stimuli.
Figure 4: Reversal of behavioral responses to natural aversive stimuli by diazepam.
Figure 5: Behavioral responses to learned aversive stimuli.

References

  1. 1

    Eysenck, M. W. in Handbook of Individual Differences: Biological Perspectives (eds. Gale, A. & Eysenck, M. W.) 157–178 (Wiley, New York, 1992).

  2. 2

    McNally, R. J. in Nebraska Symposium on Motivation Vol. 43 (eds. Dienstbier, R. A. & Hope, D. A.) 211–250 (Univ. Nebraska Press, London, 1996).

  3. 3

    Gray, J. A. & McNaughton, N. in Nebraska Symposium on Motivation Vol. 43 (eds. Dienstbier, R. A. & Hope, D. A.) 61–134 (Univ. Nebraska Press, London, 1996).

  4. 4

    Rogan, M. T. & LeDoux, J. E. Emotion: systems, cells, synaptic plasticity. Cell 85, 469– 475 (1996).

  5. 5

    Phillips, R. G. & LeDoux, J. E. Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav. Neurosci. 106, 274– 285 (1992).

  6. 6

    LeDoux, J. E. in The Cognitive Neurosciences (ed. Gazzaniga, M.) 1049– 1062 (MIT Press, Cambridge, Massachusetts, 1995).

  7. 7

    Schlegel, S. et al. Decreased benzodiazepine receptor binding in panic disorder measured by iomazenil SPECT. Eur. Arch. Psychiatry Clin. Neurosci. 244, 49–51 (1994).

  8. 8

    Kaschka, W., Feistel, H. & Ebert, D. Reduced benzodiazepine receptor binding in panic disorders measured by iomazenil SPECT. J. Psychiatr. Res. 29, 427–434 (1995).

  9. 9

    Malizia, A. L. et al. Decreased brain GABAA-benzodiazepine receptor binding in panic disorder. Arch. Gen. Psychiatry 55, 715–720 (1998).

  10. 10

    Tiihonen, J. et al. Cerebral benzodiazepine receptor binding and distribution in generalized anxiety disorder: a fractal analysis. Mol. Psychiatry. 2, 463–471 (1997).

  11. 11

    Abadie, P. et al. Relationships between trait and state anxiety and the central benzodiazepine receptor: a PET study. Eur. J. Neurosci. 11, 1470–1478 (1999).

  12. 12

    Günther, U. et al. Benzodiazepine-insensitive mice generated by targeted disruption of the γ2 subunit gene of γ-aminobutyric acid type A receptors. Proc. Natl. Acad. Sci. USA 92, 7749– 7753 (1995).

  13. 13

    Essrich, C., Lorez, M., Benson, J. A., Fritschy, J. M. & Lüscher, B. Postsynaptic clustering of major GABAA-receptor subtypes requires the γ2 subunit and gephyrin. Nat. Neurosci. 1, 563–571 (1998).

  14. 14

    Fritschy, J. M., Weinmann, O., Wenzel, A. & Benke, D. Synapse-specific localization of NMDA- and GABAA-receptor subunits revealed by antigen-retrieval immunohistochemistry. J. Comp. Neurol. 390, 194–210 (1998).

  15. 15

    Macdonald, R. L. & Olsen, R. W. GABAA-receptor channels. Annu. Rev. Neurosci. 17, 569– 602 (1994).

  16. 16

    Griebel, G., Belzung, C., Misslin, R. & Vogel, E. The free-exploratory paradigm: an effective method for measuring neophobic behavior in mice and testing neophobia-reducing drugs. Behav. Pharmacol. 4, 637–644 (1993).

  17. 17

    Lister, R. G. The use of a plus-maze to measure anxiety in the mouse. Psychopharmacology 92, 180–185 (1987).

  18. 18

    Misslin, R., Belzung, C. & Vogel, E. Behavioral validation of a light/dark choice procedure. Behav. Proc. 18, 119–132 (1989).

  19. 19

    Blanchard, D. C. & Blanchard, R. J. Ethopharmacological approaches to the biology of emotion. Annu. Rev. Psychol. 39, 43–68 (1988).

  20. 20

    Knight, R. T. Contribution of human hippocampal region to novelty detection. Nature 383, 256–259 (1996).

  21. 21

    Haefely, W. in The Challenge of Neuropharmacology (eds. Mohler, H. & DaPrada, M.) 15–40 (Roche, Basel, Switzerland, 1994).

  22. 22

    Abeliovich, A. et al. PKCγ mutant mice exhibit mild deficits in spatial and contextual learning. Cell 75, 1263– 1271 (1993).

  23. 23

    Beuzen, A. & Belzung, C. Link between emotional memory and anxiety states: a study by principal component analysis. Physiol. Behav. 58, 111–118 (1995).

  24. 24

    Mc Gaugh, J. L. Significance and remembrance: The role of neuromodulatory systems. Psychol. Sci. 1, 15–25 (1990).

  25. 25

    Panksepp, J., Sacks, D. S. & Crepeau, L. J. in Fear, Avoidance and Phobias (ed. Denny, M. R.) 7–59 (Erlbaum, Hillsdale, New Jersey, 1991).

  26. 26

    Kim, J. J., Clark, R. E. Thompson, R.F. Hippocampectomy impairs the memory of recently, but not remotely acquired trace eyeblink conditioned responses. Behav. Neurosci. 109, 195–203 (1995).

  27. 27

    Holland, P.C. in Quantitative Analyses of Behavior: Discrimination Processes (eds. Commons, M. L. et al. ) 183–206 (Ballinger, New York, 1983).

  28. 28

    McNaughton, N. Cognitive dysfunction resulting from hippocampal hyperactivity—A possible cause of anxiety disorder? Pharmacol. Biochem. Behav. 56, 603–611 (1997).

  29. 29

    Büeler, H. et al. Normal development and behavior of mice lacking the neuronal cell-surface PrP protein. Nature 356, 577–582 (1992).

  30. 30

    Beracochea, D. J. & Jaffard, R. Effects of ibotenic lesions of mammillary bodies on spontaneous and rewarded spatial alternation in mice. J. Cogn. Neurosci. 2, 133– 140 (1990).

  31. 31

    Reiman, E. M. et al. A focal brain abnormality in panic disorder, a severe form of anxiety. Nature 310, 683– 685 (1984).

  32. 32

    Nordahl, T. E. et al. Cerebral glucose metabolic differences in patients with panic disorder. Neuropsychopharmacology 3, 261–272 (1990).

  33. 33

    O'Boyle, C. A., Harris, D., Barry, H. & Cullen, J. H. Differential effects of benzodiazepine sedation in high and low anxious patients in a real life stress setting. Psychopharmacology 88, 226–229 (1986).

  34. 34

    Glue, P., Wilson, S., Coupland, N., Ball, D. & Nutt, D. The relationship between benzodiazepine receptor sensitivity and neuroticism. J. Anxiety Disord. 9, 33– 45 (1995).

  35. 35

    Holland, P.C. Brain mechanisms for changes in processing of conditional stimuli in Pavlovian conditioning: implications for behavior theory. Animal Learn. Behav. 25, 373–399 (1997).

  36. 36

    Zafra, F., Hengerer, B., Leibrock, J., Thoenen, H. & Lindholm, D. Activity-dependent regulation of BDNF and NGF mRNAs in the rat hippocampus is mediated by non-NMDA glutamate receptors. EMBO J. 9, 3545– 3550 (1990).

  37. 37

    Lüthi, A. et al. Hippocampal long-term potentiation and neural cell adhesion molecules L1 and NCAM. Nature 372, 777– 779 (1994).

  38. 38

    Carlson, S. & Willot, J. F. The behavioral salience of tones as indicated by prepulse inhibition of the startle response: relationship to hearing loss and central neural plasticity in C57BL/6J mice. Hear. Res. 99, 168–175 (1996).

  39. 39

    Hevers, W. & Lüddens, H. Diversity of GABAA-receptors. Mol. Neurobiol. 18, 35– 86 (1998).

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Acknowledgements

We thank René Misslin for advice in the preliminary experiments and Guadalupe Reyes for technical assistance. This work was supported by the Swiss National Science Foundation (grant Nr: 31-39702.93 to B.L.)

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Correspondence to Hanns Mohler.

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Crestani, F., Lorez, M., Baer, K. et al. Decreased GABAA-receptor clustering results in enhanced anxiety and a bias for threat cues. Nat Neurosci 2, 833–839 (1999). https://doi.org/10.1038/12207

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