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Ovarian cycle–linked changes in GABAA receptors mediating tonic inhibition alter seizure susceptibility and anxiety

Abstract

Disturbances of neuronal excitability changes during the ovarian cycle may elevate seizure frequency in women with catamenial epilepsy and enhance anxiety in premenstrual dysphoric disorder (PMDD). The mechanisms underlying these changes are unknown, but they could result from the effects of fluctuations in progesterone-derived neurosteroids on the brain. Neurosteroids and some anxiolytics share an important site of action: tonic inhibition mediated by δ subunit–containing GABAA receptors (δGABAARs). Here we demonstrate periodic alterations in specific GABAAR subunits during the estrous cycle in mice, causing cyclic changes of tonic inhibition in hippocampal neurons. In late diestrus (high-progesterone phase), enhanced expression of δGABAARs increases tonic inhibition, and a reduced neuronal excitability is reflected by diminished seizure susceptibility and anxiety. Eliminating cycling of δGABAARs by antisense RNA treatment or gene knockout prevents the lowering of excitability during diestrus. Our findings are consistent with possible deficiencies in regulatory mechanisms controlling normal cycling of δGABAARs in individuals with catamenial epilepsy or PMDD.

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Figure 1: Stages of the estrous cycle in C57/Bl6 mice.
Figure 2: Alterations in abundance of GABAAR subunits over the estrous cycle.
Figure 3: Tonic conductance is elevated during late diestrus in dentate gyrus granule cells.
Figure 4: Electrographic seizures vary with stages of the estrous cycle and are affected by alterations in δGABAARs.
Figure 6: Characteristics of kainic acid–induced seizures as a function of δGABAAR expression during the estrous cycle and after experimental manipulation of these subunits.
Figure 5: Decreased δGABAAR expression and tonic GABAergic inhibition after δGABAAR antisense mRNA treatment.

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References

  1. Backstrom, T. et al. Pathogenesis in menstrual cycle–linked CNS disorders. Ann. NY Acad. Sci. 1007, 42–53 (2003).

    Article  Google Scholar 

  2. Herzog, A.G., Klein, P. & Ransil, B.J. Three patterns of catamenial epilepsy. Epilepsia 38, 1082–1088 (1997).

    Article  CAS  Google Scholar 

  3. Rogawski, M.A. Progesterone, neurosteroids, and the hormonal basis of catamenial epilepsy. Ann. Neurol. 53, 288–291 (2003).

    Article  Google Scholar 

  4. Martin, J.V. & Williams, D.B. Benzodiazepine binding varies with stage of estrous cycle in unwashed membranes from mouse brain. Life Sci. 57, 1903–1909 (1995).

    Article  CAS  Google Scholar 

  5. Molina-Hernandez, M., Contreras, C.M. & Tellez-Alcantara, P. Diazepam increases the number of punished responses in a conflict-operant paradigm during late proestrus and estrus in the Wistar rat. Neuropsychobiology 43, 29–33 (2001).

    Article  CAS  Google Scholar 

  6. Reddy, D.S. & Kulkarni, S.K. Sex and estrous cycle–dependent changes in neurosteroid and benzodiazepine effects on food consumption and plus-maze learning behaviors in rats. Pharmacol. Biochem. Behav. 62, 53–60 (1999).

    Article  CAS  Google Scholar 

  7. Hevers, W. & Luddens, H. The diversity of GABAA receptors—pharmacological and electrophysiological properties of GABAA channel subtypes. Mol. Neurobiol. 18, 35–86 (1998).

    Article  CAS  Google Scholar 

  8. Mody, I. & Pearce, R.A. Diversity of inhibitory neurotransmission through GABAA receptors. Trends Neurosci. 27, 569–575 (2004).

    Article  CAS  Google Scholar 

  9. Belelli, D., Casula, A., Ling, A. & Lambert, J.J. The influence of subunit composition on the interaction of neurosteroids with GABAA receptors. Neuropharmacology 43, 651–661 (2002).

    Article  CAS  Google Scholar 

  10. Brown, N., Kerby, J., Bonnert, T.P., Whiting, P.J. & Wafford, K.A. Pharmacological characterization of a novel cell line expressing human α4β3δ GABAA receptors. Br. J. Pharmacol. 136, 965–974 (2002).

    Article  CAS  Google Scholar 

  11. Wohlfarth, K.M., Bianchi, M.T. & Macdonald, R.L. Enhanced neurosteroid potentiation of ternary GABAA receptors containing the δ subunit. J. Neurosci. 22, 1541–1549 (2002).

    Article  CAS  Google Scholar 

  12. Stell, B.M., Brickley, S.G., Tang, C.Y., Farrant, M. & Mody, I. Neuroactive steroids reduce neuronal excitability by selectively enhancing tonic inhibition mediated by δ subunit–containing GABAA receptors. Proc. Natl. Acad. Sci. USA 100, 14439–14444 (2003).

    Article  CAS  Google Scholar 

  13. Sundstrom-Poromaa, I. et al. Hormonally regulated α4β2δ GABAA receptors are a target for alcohol. Nat. Neurosci. 5, 721–722 (2002).

    Article  CAS  Google Scholar 

  14. Wallner, M., Hanchar, H.J. & Olsen, R.W. Ethanol enhances α4β3δ and α6β3δ γ-aminobutyric acid type A receptors at low concentrations known to affect humans. Proc. Natl. Acad. Sci. USA 100, 15218–15223 (2003).

    Article  CAS  Google Scholar 

  15. Wei, W.Z., Faria, L.C. & Mody, I. Low ethanol concentrations selectively augment the tonic inhibition mediated by δ subunit–containing GABAA receptors in hippocampal neurons. J. Neurosci. 24, 8379–8382 (2004).

    Article  CAS  Google Scholar 

  16. Farrant, M. & Nusser, Z. Variations on an inhibitory theme: phasic and tonic activation of GABAA receptors. Nat. Rev. Neurosci. 6, 215–229 (2005).

    Article  CAS  Google Scholar 

  17. Edwards, H.E., Burnham, W.M., Mendonca, A., Bowlby, D.A. & MacLusky, N.J. Steroid hormones affect limbic after discharge thresholds and kindling rates in adult female rats. Brain Res. 838, 136–150 (1999).

    Article  CAS  Google Scholar 

  18. Smith, M.J., Adams, L.F., Schmidt, P.J., Rubinow, D.R. & Wassermann, E.M. Effects of ovarian hormones on human cortical excitability. Ann. Neurol. 51, 599–603 (2002).

    Article  CAS  Google Scholar 

  19. Guerra-Araiza, C., Villamar-Cruz, O., Gonzalez-Arenas, A., Chavira, R. & Camacho-Arroyo, I. Changes in progesterone receptor isoforms content in the rat brain during the oestrous cycle and after oestradiol and progesterone treatments. J. Neuroendocrinol. 15, 984–990 (2003).

    Article  CAS  Google Scholar 

  20. Jones, A. et al. Ligand-gated ion channel subunit partnerships: GABAA receptor α6 subunit gene inactivation inhibits δ subunit expression. J. Neurosci. 17, 1350–1362 (1997).

    Article  CAS  Google Scholar 

  21. Sur, C. et al. Preferential coassembly of α4 and δ subunits of the γ-aminobutyric acidA receptor in rat thalamus. Mol. Pharmacol. 56, 110–115 (1999).

    Article  CAS  Google Scholar 

  22. Pirker, S., Schwarzer, C., Wieselthaler, A., Sieghart, W. & Sperk, G. GABAA receptors: immunocytochemical distribution of 13 subunits in the adult rat brain. Neuroscience 101, 815–850 (2000).

    Article  CAS  Google Scholar 

  23. Peng, Z. et al. GABAA receptor changes in δ subunit–deficient mice: altered expression of α4 and γ2 subunits in the forebrain. J. Comp. Neurol. 446, 179–197 (2002).

    Article  CAS  Google Scholar 

  24. Caraiscos, V.B. et al. Tonic inhibition in mouse hippocampal CA1 pyramidal neurons is mediated by α5 subunit–containing, γ-aminobutyric acid type A receptors. Proc. Natl. Acad. Sci. USA 101, 3662–3667 (2004).

    Article  CAS  Google Scholar 

  25. Wei, W.Z., Zhang, N.H., Peng, Z.C., Houser, C.R. & Mody, I. Perisynaptic localization of δ subunit–containing GABAA receptors and their activation by GABA spillover in the mouse dentate gyrus. J. Neurosci. 23, 10650–10661 (2003).

    Article  CAS  Google Scholar 

  26. Agmo, A. & Soria, P. GABAergic drugs and sexual motivation, receptivity and exploratory behaviors in the female rat. Psychopharmacology (Berl.) 129, 372–381 (1997).

    Article  CAS  Google Scholar 

  27. Broadbent, J. & Harless, W.E. Differential effects of GABAA and GABAB agonists on sensitization to the locomotor stimulant effects of ethanol in DBA/2 J mice. Psychopharmacology (Berl.) 141, 197–205 (1999).

    Article  CAS  Google Scholar 

  28. Mihalek, R.M. et al. Attenuated sensitivity to neuroactive steroids in γ-aminobutyrate type A receptor δ subunit knockout mice. Proc. Natl. Acad. Sci. USA 96, 12905–12910 (1999).

    Article  CAS  Google Scholar 

  29. Nyberg, S., Wahlstrom, G., Backstrom, T. & Sundstrom, P.I. Altered sensitivity to alcohol in the late luteal phase among patients with premenstrual dysphoric disorder. Psychoneuroendocrinology 29, 767–777 (2004).

    Article  CAS  Google Scholar 

  30. Smith, S.S., Ruderman, Y., Hua, G.Q. & Gulinello, M. Effects of a low dose of ethanol in an animal model of premenstrual anxiety. Alcohol 33, 41–49 (2004).

    Article  CAS  Google Scholar 

  31. Belzung, C. & Griebel, G. Measuring normal and pathological anxiety-like behaviour in mice: a review. Behav. Brain Res. 125, 141–149 (2001).

    Article  CAS  Google Scholar 

  32. Sundstrom, I. et al. Patients with premenstrual syndrome have a different sensitivity to a neuroactive steroid during the menstrual cycle compared to control subjects. Neuroendocrinology 67, 126–138 (1998).

    Article  CAS  Google Scholar 

  33. Gulinello, M., Gong, Q.H. & Smith, S.S. Progesterone withdrawal increases the α4 subunit of the GABAA receptor in male rats in association with anxiety and altered pharmacology—a comparison with female rats. Neuropharmacology 43, 701–714 (2002).

    Article  CAS  Google Scholar 

  34. Smith, S.S. et al. GABAA receptor α4 subunit suppression prevents withdrawal properties of an endogenous steroid. Nature 392, 926–930 (1998).

    Article  CAS  Google Scholar 

  35. Somogyi, P., Fritschy, J.M., Benke, D., Roberts, J.D.B. & Sieghart, W. The γ2 subunit of the GABAA receptor is concentrated in synaptic junctions containing the α1 and β2/3 subunits in hippocampus, cerebellum and globus pallidus. Neuropharmacology 35, 1425–1444 (1996).

    Article  CAS  Google Scholar 

  36. Soltesz, I., Smetters, D.K. & Mody, I. Tonic inhibition originates from synapses close to the soma. Neuron 14, 1273–1283 (1995).

    Article  CAS  Google Scholar 

  37. Sanna, E. et al. Brain steroidogenesis mediates ethanol modulation of GABAA receptor activity in rat hippocampus. J. Neurosci. 24, 6521–6530 (2004).

    Article  CAS  Google Scholar 

  38. Herzog, A.G. Progesterone therapy in women with epilepsy: a 3-year follow-up. Neurology 52, 1917–1918 (1999).

    Article  CAS  Google Scholar 

  39. Reddy, D.S. & Rogawski, M.A. Enhanced anticonvulsant activity of neuroactive steroids in a rat model of catamenial epilepsy. Epilepsia 42, 337–344 (2001).

    Article  CAS  Google Scholar 

  40. Reddy, D.S., Castaneda, D.C., O'Malley, B.W. & Rogawski, M.A. Anticonvulsant activity of progesterone and neurosteroids in progesterone receptor knockout mice. J. Pharmacol. Exp. Ther. 310, 230–239 (2004).

    Article  CAS  Google Scholar 

  41. Reddy, D.S., Kim, H.Y. & Rogawski, M.A. Neurosteroid withdrawal model of perimenstrual catamenial epilepsy. Epilepsia 42, 328–336 (2001).

    Article  CAS  Google Scholar 

  42. Smith, S.S. Withdrawal properties of a neuroactive steroid: implications for GABAA receptor gene regulation in the brain and anxiety behavior. Steroids 67, 519–528 (2002).

    Article  CAS  Google Scholar 

  43. Peng, Z.C., Huang, C.S., Stell, B.M., Mody, I. & Houser, C.R. Altered expression of the δ subunit of the GABAA receptor in a mouse model of temporal lobe epilepsy. J. Neurosci. 24, 8629–8639 (2004).

    Article  CAS  Google Scholar 

  44. Dibbens, L.M. et al. GABRD encoding a protein for extra- or peri-synaptic GABAA receptors is a susceptibility locus for generalized epilepsies. Hum. Mol. Genet. 13, 1315–1319 (2004).

    Article  CAS  Google Scholar 

  45. Lancel, M., Wetter, T.C., Steiger, A. & Mathias, S. Effect of the GABAA agonist gaboxadol on nocturnal sleep and hormone secretion in healthy elderly subjects. Am. J. Physiol. Endocrinol. Metab. 281, E130–E137 (2001).

    Article  CAS  Google Scholar 

  46. Nusser, Z. & Mody, I. Selective modulation of tonic and phasic inhibitions in dentate gyrus granule cells. J. Neurophysiol. 87, 2624–2628 (2002).

    Article  CAS  Google Scholar 

  47. Shuman, S. et al. Premenstrual dysphoric disorder in women with partial epilepsy. Epilepsia 44 (Suppl. 9): 292 (2003).

    Google Scholar 

  48. Smith, M.J., Adams, L.F., Schmidt, P.J., Rubinow, D.R. & Wassermann, E.M. Abnormal luteal phase excitability of the motor cortex in women with premenstrual syndrome. Biol. Psychiatry 54, 757–762 (2003).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank W. Sieghart (University of Vienna) for the gift of some of the antibodies used in this study. This work was supported by US National Institutes of Health grants NS30549 and NS02808 and by the Coelho Endowment to I.M. J.M was also supported by the Training Program in Neural Repair (T32 NS07449).

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Correspondence to Istvan Mody.

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Maguire, J., Stell, B., Rafizadeh, M. et al. Ovarian cycle–linked changes in GABAA receptors mediating tonic inhibition alter seizure susceptibility and anxiety. Nat Neurosci 8, 797–804 (2005). https://doi.org/10.1038/nn1469

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