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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.

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References

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

    Google Scholar 

  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).

    Google Scholar 

  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).

    Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  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).

    Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

Download references

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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