Current Literature In Basic Science
Calming Down During Coming of Age
Pubertal Expression of α4βδ GABAA Receptors Reduces Seizure-Like Discharges in CA1 Hippocampus. Yang L, Shen H, Merlin LR, Smith SS. Sci Rep 2016;6:31928. doi: 10.1038/srep31928.
More than half of children with epilepsy outgrow their seizures, yet the underlying mechanism is unknown. GABAergic inhibition increases at puberty in female mice due to expression of extrasynaptic α4βδ GABAA receptors (GABARs). Therefore, we tested the role of these receptors in regulating seizure-like discharges in CA1 hippocampus using a high K+ (8.5 mM) seizure model. Spontaneous field potentials were recorded from hippocampus of pre-pubertal (~28–32 PND) and pubertal (~35–44 PND) female wild-type or α4−/− mice. The coastline length, a measure of burst intensity, was assessed. 8.5 mM K+ induced seizure-like discharges in over 60% of pre-pubertal slices, but only in 7% of pubertal slices, where the coastline length was reduced by 70% (P = 0.04). However, the pubertal decrease in seizure-like discharges was not seen in the α4−/−, implicating α4βδ GABARs as the cause of the decreased seizure-like activity during puberty. Administration of THIP or DS2, to selectively increase α4βδ current, reduced activity in 8.5 mM K+ at puberty, while blockade of α5-GABARs had no effect. GABAergic current was depolarizing but inhibitory in 8.5 mM K+, suggesting a mechanism for the effects of α4βδ and α5-GABARs, which exhibit different polarity-dependent desensitization. These data suggest that α4βδ GABARs are anti-convulsant during adolescence.
Commentary Epilepsy is the most common neurological disease in children. The prevalence of epilepsy in children has been reported to range from 1.5 to 121 per 1,000 (1–4), the variability of which results from differences due to socioeconomic and geographical factors—with an increased incidence in rural populations and developing countries—as well as differences in study design and methodologies used to diagnose epilepsy in children. Information regarding the natural history of epilepsy (for review see [5]) is not only valuable for the evaluating treatment strategies and informing the patient and family but may also provide insight into understanding the underlying neurobiology. In general, the prognosis of many childhood epilepsies is good, with overall remission rates of 70 to 80 percent (6). However, approximately 30% of childhood epilepsies continue into adulthood. The concept of spontaneous remission of epilepsy has been somewhat controversial, given the introduction of effective pharmacotherapy for epilepsy while leaving the natural history of untreated epilepsy largely unknown. However, it is widely accepted that current antiepileptic drugs (AEDs) are antiseizure treatments rather than antiepileptogenic, indicating that these drugs do not alter the disease process or progression. The lack of antiepileptogenic effects of current treatments and the similar incidence of seizure remission in countries with limited access to AEDs (for Epilepsy Currents, Vol. 17, No. 1 (January/February) 2017 pp. 57–59 © American Epilepsy Society
review see [5]) suggest that seizure remission is spontaneous in many cases of childhood epilepsies. This leaves us with important unanswered questions regarding why some seizures remit while others persist. This question necessitates a better understanding of the mechanisms underlying seizures remission. Unfortunately, very few studies have investigated the mechanisms underlying seizure remission in childhood epilepsies. One study identified a gene associated with remitting focal epilepsy in dogs (7), Lgi2, which is a homologue of the human epilepsy gene LGI1. Lgi2, like LGI1, plays a role in synapse remodeling and investigation into the impact of the epilepsy-associated mutations on synaptic transmission throughout development may provide insight into spontaneously remitting childhood epilepsy. Here, we highlight a recent study by Yang et al. implicating extrasynaptic GABAA receptors (GABAARs) in mediating the decrease in seizure susceptibility during adolescence. A previous study from this group demonstrated a dramatic increase in expression of the α4 and δ subunits of the GABAAR on CA1 pyramidal neurons at puberty (8, 9). Functionally, these observed changes during puberty result in increased tonic inhibition in CA1 pyramidal cells (9); even though these currents have been shown to be outward (8), the net effect is still inhibitory via shunting inhibition. In the highlighted manuscript, Yang et al. demonstrated decreased epileptiform activity induced with elevated extracellular K+ (8.5 mM) at puberty (~35–44 PND) compared to prepubertal mice (~28–32 PND). The change in excitability in mice at puberty is thought to be due to increased expression of α4 and δ subunits of the GABAAR on CA1 pyramidal neurons (9), which is corroborat-
57
The Excitement of Puberty
ed in Yang et al. with evidence demonstrating that preferentially potentiating the effects of GABA on these receptors with either THIP or DS2 decreased epileptiform activity at puberty, but not in prepubertal mice. Further supporting a role for α4-containing GABAARs in seizure remission is the evidence that there is no difference in epileptiform activity in α4-/- mice at puberty compared to prepubertal mice. However, blocking other extrasynaptic subtypes of GABAARs (α5) or synaptic receptors did not have differential effects on excitability in slices from mice at puberty or in prepubertal animals. These data implicate developmental alterations in specific GABAAR subtypes in mediating the changes in excitability in the transition from childhood to adolescence; this may have implications for remission of childhood epilepsies. If extrasynaptic GABAARs play a role in remission in childhood epilepsies, one would anticipate that mutations in these receptors may be associated with epilepsy. In fact, two missense mutations have been identified in the gene encoding for the GABAAR δ subunit,GABRD, in association with GEFS+ and IGE (10, 11). However, there are likely numerous, diverse mechanisms contributing to the presentation and remission of childhood epilepsies. The study highlighted here suggests that the developmental profile of specific GABAAR subtypes may play a role in these processes. Given that these receptors are sensitive to neurosteroid potentiation, one must also consider the developmental changes in neurosteroid levels (12, 13) that have been shown to influence network excitability and seizure susceptibility (14). In fact, relevant to the currently highlighted study, developmental changes in neurosteroid levels, including a reduction in endogenous neurosteroid tone leading up to puberty (15), may underlie the observed pubertal changes in GABAAR subunit composition (16), since allopregnanolone withdrawal has been shown to increase expression of α4 and δ subunits (for review see [17]). However, in the absence of compensatory GABAAR remodeling, the developmental decrease in neurosteroid tone could potentially have proexcitatory effects. This study focuses on the role of neurosteroid-sensitive GABAARs in excitability changes during puberty; however, these fundamental concepts translate to other conditions characterized by fluctuations in neurosteroid levels, such as over the estrous cycle in adult female rodents. Changes in the expression of the δ and α4 subunits of the GABAAR have been observed over the estrous cycle (18-20) and have been demonstrated to underlie changes in excitability over the estrous cycle (19). Dysregulation in neurosteroid-mediated regulation of GABAAR has been suggested to contribute to the catamenial form of epilepsy (21), in which some women with epilepsy experience a pattern of seizure exacerbation related to their menstrual cycle. Although catamenial epilepsy is a female-specific condition, neurosteroid-mediated regulation of GABAARs has also been observed in males (22). In fact, the neurosteroid regulation of GABAARs is not limited to ovarian-derived neurosteroids as similar changes have been observed with stress-derived neurosteroids (22). In addition, androgens are known to have antiseizure effects and similar to ovarian-derived neurosteroid, allopregnanolone, the testosterone-derived neurosteroid androstanediol is a positive allosteric modulator of GABAARs
58
(23). Although the impact of hormones and hormone derivatives have been explored to a lesser extent in males, based on this evidence, it is likely that developmental changes in neurosteroids and the expression of extrasynaptic GABAARs, in which these modulators preferentially act, also plays a role in seizure remission in childhood epilepsy in males. This currently highlighted study provides promising evidence for a potential mechanism underlying the remission of childhood epilepsies. However, there has been very limited investigation into the mechanisms underlying the remission of childhood epilepsies, and these studies are in their infancy. Future studies are necessary in both patients and animal models to fully understand the contribution of these receptors and developmental changes in neurosteroid levels to the natural progression of childhood epilepsy. by Jamie Maguire, PhD References 1. Sidenvall R, Forsgren L, Heijbel J. Prevalence and characteristics of epilepsy in children in Northern Sweden. Seizure 1996;5:139–146. 2. Cowan LD, Bodensteiner JB, Leviton A, Doherty L. Prevalence of the epilepsies in children and adolescents. Epilepsia 1989;30:94–106. 3. Hauser WA. The prevalence and incidence of convulsive disorders in children. Epilepsia 1994;35(suppl 2):S1–S6. 4. Eriksson KJ, Koivikko MJ. Prevalence, classification, and severity of epilepsy and epileptic syndromes in children. Epilepsia 1997;38:1275– 1282. 5. Kwan P, Sander J. The natural history of epilepsy: An epidemiological view. J Neurol Neurosurg Psychiatry 2004;75:1376–1381. 6. Berg AT, Shinnar S. The contributions of epidemiology to the understanding of childhood seizures and epilepsy. J Child Neurol 1994;9(suppl 2):19–26. 7. Seppala EH, Jokinen TS, Fukata M, Fukata Y, Webster MT, Karlsson EK, Kilpinen SK, Steffen F, Dietschi E, Leeb T, Eklund R, Zhao X, Rilstone JJ, Lindblad-Toh K, Minassian BA, Lohi H. Lgi2 truncation causes a remitting focal epilepsy in dogs. PLoS Genetics 2011;7:e1002194. 8. Shen H, Sabaliauskas N, Sherpa A, Fenton AA, Stelzer A, Aoki C, Smith SS. A critical role for α4βδ GABAA receptors in shaping learning deficits at puberty in mice. Science 2010;327:1515–1518. 9. Shen H, Gong QH, Aoki C, Yuan M, Ruderman Y, Dattilo M, Williams K, Smith SS. Reversal of neurosteroid effects at α4βδ GABAA receptors triggers anxiety at puberty. Nat Neurosci 2007;10:469–477. 10. Dibbens LM, Feng HJ, Richards MC, Harkin LA, Hodgson BL, Scott D, Jenkins M, Petrou S, Sutherland GR, Scheffer IE, Berkovic SF, Macdonald RL, Mulley JC. GABRD encoding a protein for extra- or peri-synaptic GABAA receptors is a susceptibility locus for generalized epilepsies. Hum Mol Genet 2004;13:1315–1319. 11. Mulley JC, Scheffer IE, Harkin LA, Berkovic SF, Dibbens LM. Susceptibility genes for complex epilepsy. Hum Mol Genet 2005;14:R243–R249. 12. Genazzani AR, Bernardi F, Monteleone P, Luisi S, Luisi M. Neuropeptides, neurotransmitters, neurosteroids, and the onset of puberty. Ann N Y Acad Sci 2000;900:1–9. 13. Brown AR, Mitchell SJ, Peden DR, Herd MB, Seifi M, Swinny JD, Belelli D, Lambert JJ. During postnatal development endogenous neurosteroids influence GABA-ergic neurotransmission of mouse cortical neurons. Neuropharmacology 2016;103:163–173. 14. Reddy DS. Neurosteroids: Endogenous role in the human brian and therapeutic potentials. Prog Brain Res 2010;186:113–137.
The Excitement of Puberty
15. Brown AR, Mitchell SJ, Peden DR et al. During postnatal development endogenous neurosteroids influence GABA-ergic neurotransmission of mouse cortical neurons. Neuropharmacology 2016;103:163-73. 16. Shen H, Gong QH, Aoki C et al. Reversal of neurosteroid effects at alpha4beta2delta GABAA receptors triggers anxiety at puberty. Nat Neurosci 2007;10:469-77. 17. Smith SS, Shen H, Gong QH, Zhou X. Neurosteroid regulation of GABA(A) receptors: Focus on the alpha4 and delta subunits. Pharmacol Ther 2007;116:58-76. 18. Lovick TA. Plasticity of GABAA receptor subunit expression during the oestrous cycle of the rat: implications for premenstrual syndrome in women. Exp Physiol 2006;91:655-60. 19. Maguire JL, Stell BM, Rafizadeh M, Mody I. Ovarian cycle-linked changes in GABA(A) receptors mediating tonic inhibition alter seizure susceptibility and anxiety. Nat Neurosci 2005;8:797-804.
20. Wu X, Gangisetty O, Carver CM, Reddy DS. Estrous cycle regulation of extrasynaptic delta-containing GABA(A) receptor-mediated tonic inhibition and limbic epileptogenesis. J Pharmacol Exp Ther 2013;346:146-60. 21. Reddy DS. Catamenial Epilepsy: Discovery of an Extrasynaptic Molecular Mechanism for Targeted Therapy. Frontiers in Cellular Neuroscience 2016;10:101. 22. Maguire J, Mody I. Neurosteroid synthesis-mediated regulation of GABA(A) receptors: relevance to the ovarian cycle and stress. J Neurosci 2007;27:2155-62. 23. Reddy DS, Jian K. The Testosterone-Derived Neurosteroid Androstanediol Is a Positive Allosteric Modulator of GABA(A) Receptors. The Journal of Pharmacology and Experimental Therapeutics 2010;334:1031-41.
59
Calming Down During Coming of Age
Pubertal Expression of α4βδ GABAA Receptors Reduces Seizure-Like Discharges in CA1 Hippocampus. Yang L, Shen H, Merlin LR, Smith SS. Sci Rep 2016;6:31928. doi: 10.1038/srep31928.
More than half of children with epilepsy outgrow their seizures, yet the underlying mechanism is unknown. GABAergic inhibition increases at puberty in female mice due to expression of extrasynaptic α4βδ GABAA receptors (GABARs). Therefore, we tested the role of these receptors in regulating seizure-like discharges in CA1 hippocampus using a high K+ (8.5 mM) seizure model. Spontaneous field potentials were recorded from hippocampus of pre-pubertal (~28–32 PND) and pubertal (~35–44 PND) female wild-type or α4−/− mice. The coastline length, a measure of burst intensity, was assessed. 8.5 mM K+ induced seizure-like discharges in over 60% of pre-pubertal slices, but only in 7% of pubertal slices, where the coastline length was reduced by 70% (P = 0.04). However, the pubertal decrease in seizure-like discharges was not seen in the α4−/−, implicating α4βδ GABARs as the cause of the decreased seizure-like activity during puberty. Administration of THIP or DS2, to selectively increase α4βδ current, reduced activity in 8.5 mM K+ at puberty, while blockade of α5-GABARs had no effect. GABAergic current was depolarizing but inhibitory in 8.5 mM K+, suggesting a mechanism for the effects of α4βδ and α5-GABARs, which exhibit different polarity-dependent desensitization. These data suggest that α4βδ GABARs are anti-convulsant during adolescence.
Commentary Epilepsy is the most common neurological disease in children. The prevalence of epilepsy in children has been reported to range from 1.5 to 121 per 1,000 (1–4), the variability of which results from differences due to socioeconomic and geographical factors—with an increased incidence in rural populations and developing countries—as well as differences in study design and methodologies used to diagnose epilepsy in children. Information regarding the natural history of epilepsy (for review see [5]) is not only valuable for the evaluating treatment strategies and informing the patient and family but may also provide insight into understanding the underlying neurobiology. In general, the prognosis of many childhood epilepsies is good, with overall remission rates of 70 to 80 percent (6). However, approximately 30% of childhood epilepsies continue into adulthood. The concept of spontaneous remission of epilepsy has been somewhat controversial, given the introduction of effective pharmacotherapy for epilepsy while leaving the natural history of untreated epilepsy largely unknown. However, it is widely accepted that current antiepileptic drugs (AEDs) are antiseizure treatments rather than antiepileptogenic, indicating that these drugs do not alter the disease process or progression. The lack of antiepileptogenic effects of current treatments and the similar incidence of seizure remission in countries with limited access to AEDs (for Epilepsy Currents, Vol. 17, No. 1 (January/February) 2017 pp. 57–59 © American Epilepsy Society
review see [5]) suggest that seizure remission is spontaneous in many cases of childhood epilepsies. This leaves us with important unanswered questions regarding why some seizures remit while others persist. This question necessitates a better understanding of the mechanisms underlying seizures remission. Unfortunately, very few studies have investigated the mechanisms underlying seizure remission in childhood epilepsies. One study identified a gene associated with remitting focal epilepsy in dogs (7), Lgi2, which is a homologue of the human epilepsy gene LGI1. Lgi2, like LGI1, plays a role in synapse remodeling and investigation into the impact of the epilepsy-associated mutations on synaptic transmission throughout development may provide insight into spontaneously remitting childhood epilepsy. Here, we highlight a recent study by Yang et al. implicating extrasynaptic GABAA receptors (GABAARs) in mediating the decrease in seizure susceptibility during adolescence. A previous study from this group demonstrated a dramatic increase in expression of the α4 and δ subunits of the GABAAR on CA1 pyramidal neurons at puberty (8, 9). Functionally, these observed changes during puberty result in increased tonic inhibition in CA1 pyramidal cells (9); even though these currents have been shown to be outward (8), the net effect is still inhibitory via shunting inhibition. In the highlighted manuscript, Yang et al. demonstrated decreased epileptiform activity induced with elevated extracellular K+ (8.5 mM) at puberty (~35–44 PND) compared to prepubertal mice (~28–32 PND). The change in excitability in mice at puberty is thought to be due to increased expression of α4 and δ subunits of the GABAAR on CA1 pyramidal neurons (9), which is corroborat-
57
The Excitement of Puberty
ed in Yang et al. with evidence demonstrating that preferentially potentiating the effects of GABA on these receptors with either THIP or DS2 decreased epileptiform activity at puberty, but not in prepubertal mice. Further supporting a role for α4-containing GABAARs in seizure remission is the evidence that there is no difference in epileptiform activity in α4-/- mice at puberty compared to prepubertal mice. However, blocking other extrasynaptic subtypes of GABAARs (α5) or synaptic receptors did not have differential effects on excitability in slices from mice at puberty or in prepubertal animals. These data implicate developmental alterations in specific GABAAR subtypes in mediating the changes in excitability in the transition from childhood to adolescence; this may have implications for remission of childhood epilepsies. If extrasynaptic GABAARs play a role in remission in childhood epilepsies, one would anticipate that mutations in these receptors may be associated with epilepsy. In fact, two missense mutations have been identified in the gene encoding for the GABAAR δ subunit,GABRD, in association with GEFS+ and IGE (10, 11). However, there are likely numerous, diverse mechanisms contributing to the presentation and remission of childhood epilepsies. The study highlighted here suggests that the developmental profile of specific GABAAR subtypes may play a role in these processes. Given that these receptors are sensitive to neurosteroid potentiation, one must also consider the developmental changes in neurosteroid levels (12, 13) that have been shown to influence network excitability and seizure susceptibility (14). In fact, relevant to the currently highlighted study, developmental changes in neurosteroid levels, including a reduction in endogenous neurosteroid tone leading up to puberty (15), may underlie the observed pubertal changes in GABAAR subunit composition (16), since allopregnanolone withdrawal has been shown to increase expression of α4 and δ subunits (for review see [17]). However, in the absence of compensatory GABAAR remodeling, the developmental decrease in neurosteroid tone could potentially have proexcitatory effects. This study focuses on the role of neurosteroid-sensitive GABAARs in excitability changes during puberty; however, these fundamental concepts translate to other conditions characterized by fluctuations in neurosteroid levels, such as over the estrous cycle in adult female rodents. Changes in the expression of the δ and α4 subunits of the GABAAR have been observed over the estrous cycle (18-20) and have been demonstrated to underlie changes in excitability over the estrous cycle (19). Dysregulation in neurosteroid-mediated regulation of GABAAR has been suggested to contribute to the catamenial form of epilepsy (21), in which some women with epilepsy experience a pattern of seizure exacerbation related to their menstrual cycle. Although catamenial epilepsy is a female-specific condition, neurosteroid-mediated regulation of GABAARs has also been observed in males (22). In fact, the neurosteroid regulation of GABAARs is not limited to ovarian-derived neurosteroids as similar changes have been observed with stress-derived neurosteroids (22). In addition, androgens are known to have antiseizure effects and similar to ovarian-derived neurosteroid, allopregnanolone, the testosterone-derived neurosteroid androstanediol is a positive allosteric modulator of GABAARs
58
(23). Although the impact of hormones and hormone derivatives have been explored to a lesser extent in males, based on this evidence, it is likely that developmental changes in neurosteroids and the expression of extrasynaptic GABAARs, in which these modulators preferentially act, also plays a role in seizure remission in childhood epilepsy in males. This currently highlighted study provides promising evidence for a potential mechanism underlying the remission of childhood epilepsies. However, there has been very limited investigation into the mechanisms underlying the remission of childhood epilepsies, and these studies are in their infancy. Future studies are necessary in both patients and animal models to fully understand the contribution of these receptors and developmental changes in neurosteroid levels to the natural progression of childhood epilepsy. by Jamie Maguire, PhD References 1. Sidenvall R, Forsgren L, Heijbel J. Prevalence and characteristics of epilepsy in children in Northern Sweden. Seizure 1996;5:139–146. 2. Cowan LD, Bodensteiner JB, Leviton A, Doherty L. Prevalence of the epilepsies in children and adolescents. Epilepsia 1989;30:94–106. 3. Hauser WA. The prevalence and incidence of convulsive disorders in children. Epilepsia 1994;35(suppl 2):S1–S6. 4. Eriksson KJ, Koivikko MJ. Prevalence, classification, and severity of epilepsy and epileptic syndromes in children. Epilepsia 1997;38:1275– 1282. 5. Kwan P, Sander J. The natural history of epilepsy: An epidemiological view. J Neurol Neurosurg Psychiatry 2004;75:1376–1381. 6. Berg AT, Shinnar S. The contributions of epidemiology to the understanding of childhood seizures and epilepsy. J Child Neurol 1994;9(suppl 2):19–26. 7. Seppala EH, Jokinen TS, Fukata M, Fukata Y, Webster MT, Karlsson EK, Kilpinen SK, Steffen F, Dietschi E, Leeb T, Eklund R, Zhao X, Rilstone JJ, Lindblad-Toh K, Minassian BA, Lohi H. Lgi2 truncation causes a remitting focal epilepsy in dogs. PLoS Genetics 2011;7:e1002194. 8. Shen H, Sabaliauskas N, Sherpa A, Fenton AA, Stelzer A, Aoki C, Smith SS. A critical role for α4βδ GABAA receptors in shaping learning deficits at puberty in mice. Science 2010;327:1515–1518. 9. Shen H, Gong QH, Aoki C, Yuan M, Ruderman Y, Dattilo M, Williams K, Smith SS. Reversal of neurosteroid effects at α4βδ GABAA receptors triggers anxiety at puberty. Nat Neurosci 2007;10:469–477. 10. Dibbens LM, Feng HJ, Richards MC, Harkin LA, Hodgson BL, Scott D, Jenkins M, Petrou S, Sutherland GR, Scheffer IE, Berkovic SF, Macdonald RL, Mulley JC. GABRD encoding a protein for extra- or peri-synaptic GABAA receptors is a susceptibility locus for generalized epilepsies. Hum Mol Genet 2004;13:1315–1319. 11. Mulley JC, Scheffer IE, Harkin LA, Berkovic SF, Dibbens LM. Susceptibility genes for complex epilepsy. Hum Mol Genet 2005;14:R243–R249. 12. Genazzani AR, Bernardi F, Monteleone P, Luisi S, Luisi M. Neuropeptides, neurotransmitters, neurosteroids, and the onset of puberty. Ann N Y Acad Sci 2000;900:1–9. 13. Brown AR, Mitchell SJ, Peden DR, Herd MB, Seifi M, Swinny JD, Belelli D, Lambert JJ. During postnatal development endogenous neurosteroids influence GABA-ergic neurotransmission of mouse cortical neurons. Neuropharmacology 2016;103:163–173. 14. Reddy DS. Neurosteroids: Endogenous role in the human brian and therapeutic potentials. Prog Brain Res 2010;186:113–137.
The Excitement of Puberty
15. Brown AR, Mitchell SJ, Peden DR et al. During postnatal development endogenous neurosteroids influence GABA-ergic neurotransmission of mouse cortical neurons. Neuropharmacology 2016;103:163-73. 16. Shen H, Gong QH, Aoki C et al. Reversal of neurosteroid effects at alpha4beta2delta GABAA receptors triggers anxiety at puberty. Nat Neurosci 2007;10:469-77. 17. Smith SS, Shen H, Gong QH, Zhou X. Neurosteroid regulation of GABA(A) receptors: Focus on the alpha4 and delta subunits. Pharmacol Ther 2007;116:58-76. 18. Lovick TA. Plasticity of GABAA receptor subunit expression during the oestrous cycle of the rat: implications for premenstrual syndrome in women. Exp Physiol 2006;91:655-60. 19. Maguire JL, Stell BM, Rafizadeh M, Mody I. Ovarian cycle-linked changes in GABA(A) receptors mediating tonic inhibition alter seizure susceptibility and anxiety. Nat Neurosci 2005;8:797-804.
20. Wu X, Gangisetty O, Carver CM, Reddy DS. Estrous cycle regulation of extrasynaptic delta-containing GABA(A) receptor-mediated tonic inhibition and limbic epileptogenesis. J Pharmacol Exp Ther 2013;346:146-60. 21. Reddy DS. Catamenial Epilepsy: Discovery of an Extrasynaptic Molecular Mechanism for Targeted Therapy. Frontiers in Cellular Neuroscience 2016;10:101. 22. Maguire J, Mody I. Neurosteroid synthesis-mediated regulation of GABA(A) receptors: relevance to the ovarian cycle and stress. J Neurosci 2007;27:2155-62. 23. Reddy DS, Jian K. The Testosterone-Derived Neurosteroid Androstanediol Is a Positive Allosteric Modulator of GABA(A) Receptors. The Journal of Pharmacology and Experimental Therapeutics 2010;334:1031-41.
59
