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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References
Backstrom, T. et al. Pathogenesis in menstrual cycle–linked CNS disorders. Ann. NY Acad. Sci. 1007, 42–53 (2003).
Herzog, A.G., Klein, P. & Ransil, B.J. Three patterns of catamenial epilepsy. Epilepsia 38, 1082–1088 (1997).
Rogawski, M.A. Progesterone, neurosteroids, and the hormonal basis of catamenial epilepsy. Ann. Neurol. 53, 288–291 (2003).
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).
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).
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).
Hevers, W. & Luddens, H. The diversity of GABAA receptors—pharmacological and electrophysiological properties of GABAA channel subtypes. Mol. Neurobiol. 18, 35–86 (1998).
Mody, I. & Pearce, R.A. Diversity of inhibitory neurotransmission through GABAA receptors. Trends Neurosci. 27, 569–575 (2004).
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).
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).
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).
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).
Sundstrom-Poromaa, I. et al. Hormonally regulated α4β2δ GABAA receptors are a target for alcohol. Nat. Neurosci. 5, 721–722 (2002).
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).
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).
Farrant, M. & Nusser, Z. Variations on an inhibitory theme: phasic and tonic activation of GABAA receptors. Nat. Rev. Neurosci. 6, 215–229 (2005).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Agmo, A. & Soria, P. GABAergic drugs and sexual motivation, receptivity and exploratory behaviors in the female rat. Psychopharmacology (Berl.) 129, 372–381 (1997).
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).
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).
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).
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).
Belzung, C. & Griebel, G. Measuring normal and pathological anxiety-like behaviour in mice: a review. Behav. Brain Res. 125, 141–149 (2001).
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).
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).
Smith, S.S. et al. GABAA receptor α4 subunit suppression prevents withdrawal properties of an endogenous steroid. Nature 392, 926–930 (1998).
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).
Soltesz, I., Smetters, D.K. & Mody, I. Tonic inhibition originates from synapses close to the soma. Neuron 14, 1273–1283 (1995).
Sanna, E. et al. Brain steroidogenesis mediates ethanol modulation of GABAA receptor activity in rat hippocampus. J. Neurosci. 24, 6521–6530 (2004).
Herzog, A.G. Progesterone therapy in women with epilepsy: a 3-year follow-up. Neurology 52, 1917–1918 (1999).
Reddy, D.S. & Rogawski, M.A. Enhanced anticonvulsant activity of neuroactive steroids in a rat model of catamenial epilepsy. Epilepsia 42, 337–344 (2001).
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).
Reddy, D.S., Kim, H.Y. & Rogawski, M.A. Neurosteroid withdrawal model of perimenstrual catamenial epilepsy. Epilepsia 42, 328–336 (2001).
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).
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).
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).
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).
Nusser, Z. & Mody, I. Selective modulation of tonic and phasic inhibitions in dentate gyrus granule cells. J. Neurophysiol. 87, 2624–2628 (2002).
Shuman, S. et al. Premenstrual dysphoric disorder in women with partial epilepsy. Epilepsia 44 (Suppl. 9): 292 (2003).
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).
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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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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DOI: https://doi.org/10.1038/nn1469
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