GABAA receptor modulation by neurosteroids in models of temporal lobe epilepsies

Epilepsia (Impact Factor: 4.57). 12/2012; 53(s9). DOI: 10.1111/epi.12038


Epilepsies consist of a spectrum of neurologic disorders typically characterized by unpredictable and dysfunctional network behaviors in the central nervous system (CNS), which lead to discrete episodes of large bouts of uncontrolled neuronal synchrony that interfere with the normal functioning of the brain. Temporal lobe epilepsy (TLE) is accompanied by changes in interneuronal innervation and modifications in different γ-aminobutyric acid (GABA)A receptor subunits. Hormones play an important role in modulating the overall excitability of neurons, and at the same time hormonal pathways are frequently modified during epilepsy. This review focuses on TLE-correlated modifications of GABAergic transmission, and in particular on the implications of some of our own findings related to GABAARs containing the δ subunits (δ-GABAARs). These are extra- or perisynaptic GABAARs that mediate tonic inhibition, a major component of the inhibitory mechanism in the brain. The most potent endogenous modulators of δ-GABAARs are neurosteroids, which act as positive allosteric modulators. Plasticity of δ-GABAARs during TLE consists of down-regulation of the subunit in the dentate gyrus granule cells (DGGCs), while being up-regulated in interneurons. Surprisingly, the level of tonic inhibition in DGGCs remains unchanged, consistent with the idea that it becomes mediated by GABAARs containing other subunits. In parallel, tonic inhibition in a TLE model ceases to be sensitive to neurosteroid potentiation. In contrast, as predicted by the anatomic plasticity, interneuronal tonic current is increased, and remains sensitive to neurosteroids. These findings have important pharmacologic implications. Where neurosteroids normally have sedative and anticonvulsant effects, bimodal and cell-type specific modulations in their natural targets might weaken the inhibitory control on the dentate gate, under circumstances of altered neurosteroids levels (stress, ovarian cycle, or the postpartum period).

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    • "This is interesting because the same appears to occur in catamenial epilepsy, where seizure exacerbation is not always at the same cycle stage (Herzog et al., 1997). Seizure exacerbation during the periovulatory period is considered to be caused by rising levels of 17β-estradiol, and the increased severity of seizures during the perimenstrual period is commonly explained by declining levels of progesterone and its metabolite, allopregnanolone (Verrotti et al., 2010; Maguire et al., 2005; Reddy and Rogawski, 2012; Ferando and Mody, 2012; Reddy and Rogawski, 2009; Joshi et al., 2013; Smith et al., 2007; Biagini et al., 2010; Biagini et al., 2012). "
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    ABSTRACT: In catamenial epilepsy, seizures exhibit a cyclic pattern that parallels the menstrual cycle. Many studies suggest that catamenial seizures are caused by fluctuations in gonadal hormones during the menstrual cycle, but this has been difficult to study in rodent models of epilepsy because the ovarian cycle in rodents, called the estrous cycle, is disrupted by severe seizures. Thus, when epilepsy is severe, estrous cycles become irregular or stop. Therefore, we modified kainic acid (KA)- and pilocarpine-induced status epilepticus (SE) models of epilepsy so that seizures were rare for the first months after SE, and conducted video-EEG during this time. The results showed that interictal spikes (IIS) occurred intermittently. All rats with regular 4-day estrous cycles had IIS that waxed and waned with the estrous cycle. The association between the estrous cycle and IIS was strong: if the estrous cycles became irregular transiently, IIS frequency also became irregular, and when the estrous cycle resumed its 4-day pattern, IIS frequency did also. Furthermore, when rats were ovariectomized, or males were recorded, IIS frequency did not show a 4-day pattern. Systemic administration of an estrogen receptor antagonist stopped the estrous cycle transiently, accompanied by transient irregularity of the IIS pattern. Eventually all animals developed severe, frequent seizures and at that time both the estrous cycle and the IIS became irregular. We conclude that the estrous cycle entrains IIS in the modified KA and pilocarpine SE models of epilepsy. The data suggest that the ovarian cycle influences more aspects of epilepsy than seizure susceptibility. Copyright © 2015. Published by Elsevier Inc.
    Experimental Neurology 04/2015; 269. DOI:10.1016/j.expneurol.2015.04.003 · 4.70 Impact Factor
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    • "However, without such studies, treatment of patients with epilepsy will be adversely affected. For example, a drug that acts on GABA A receptors may always have effects in males, but not be as consistent in women because at the end of the luteal phase of her menstrual cycle there are changes in GABA A receptor subunits (Ferando and Mody, 2012; Maguire et al., 2005; Smith et al., 2007). Substantial sex differences may exist in drugs that act on muscarinic receptors. "
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    ABSTRACT: When all of the epilepsies are considered, sex differences are not always clear, despite the fact that many sex differences are known in the normal brain. Sex differences in epilepsy in laboratory animals are also unclear, although robust effects of sex on seizures have been reported, and numerous effects of gonadal steroids have been shown throughout the rodent brain. Here we discuss several reasons why sex differences in seizure susceptibility are unclear or are difficult to study. Examples of robust sex differences in laboratory rats, such as the relative resistance of adult female rats to the chemoconvulsant pilocarpine compared to males, are described. We also describe a novel method that has shed light on sex differences in neuropathology, which is a relatively new techniques that will potentially contribute to sex differences research in the future. The assay we highlight uses the neuronal nuclear antigen NeuN to probe sex differences in adult male and female rats and mice. In females, weak NeuN expression defines a sex difference that previous neuropathological studies have not described. We also show that in adult rats, social isolation stress can obscure the normal effects of 17β-estradiol to increase excitability in area CA3 of hippocampus. These data underscore the importance of controlling behavioral stress in studies of seizure susceptibility in rodents and suggest that behavioral stress may be one factor that has led to inconsistencies in outcomes of sex differences research. These and other issues have made it difficult to translate our increasing knowledge about the effects of gonadal hormones on the brain to improved treatment for men and women with epilepsy.
    Neurobiology of Disease 07/2014; 72. DOI:10.1016/j.nbd.2014.07.004 · 5.08 Impact Factor
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    • "GABAA receptors contain γ subunits that mediate tonic inhibition in the central nervous system. The most potent endogenous modulators of GABAA receptors are neurosteroids that act as positive allosteric modulators (31). However, the exact mechanism(s) underlying the regulation of GABA subunit gene expression by neurosteroids has not been fully clarified and needs to be studied in future investigation. "
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    ABSTRACT: Objective(s): Painful diabetic neuropathy is associated with hyperexcitability and hyperactivity of spinal cord neurons. However, its underlying pathophysiological mechanisms have not been fully clarified. Induction of excitatory/inhibitory neurotransmission imbalance at the spinal cord seems to account for the abnormal neuronal activity in diabetes. Protective properties of neurosteroids have been demonstrated in numerous cellular and animal models of neurodegeneration. Materials and Methods: Here, the protective effects of allopregnanolone, a neurosteroid were investigated in an in vivo model of diabetic neuropathy. The tail-flick test was used to assess the nociceptive threshold. Diabetes was induced by injection of 50 mg/kg (IP) streptozotocin. Seven weeks after the induction of diabetes, the dorsal half of the lumbar spinal cord was assayed for the expression of γ2 subunit of GABAA receptor using semiquantitative RT-PCR. Results: The data shows that allopregnanolone (5 and 20 mg/kg) markedly ameliorated diabetes-induced thermal hyperalgesia and motor deficit. The weights of diabetic rats that received 5 and 20 mg/kg allopregnanolone did not significantly reduce during the time course of study. Furthermore, this neurosteroid could inhibit GABAA receptor down-regulation induced by diabetes in the rat spinal cord. Conclusion: The data revealed that allopregnanolone has preventive effects against hyperglycemic-induced neuropathic pain and motor deficit which are related to the inhibition of GABAA receptor down-regulation.
    Iranian Journal of Basic Medical Sciences 05/2014; 17(5):312-7. · 1.23 Impact Factor
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