Sleep deprivation: a risk for epileptic seizures

There is a well-documented correlation between epilepsy and sleep deprivation. For decades, preclinical and clinical studies have shown that sleep deprivation can lead to an increased risk of epileptic seizures. Additionally, sleep deprivation has been used clinically as a diagnostic tool for epilepsy by triggering epileptiform activity. However, an underlying mechanism for this relationship is yet to be confirmed. Interestingly, a decrease in gamma-aminobutyric acid (GABA)-mediated tonic inhibition has been shown in both epilepsy and sleep deprivation. This review focuses on the role of sleep deprivation in the induction of epileptic seizures and the possible role of reduced GABA receptor expression in the sleep-deprived state.

Epilepsy - Sleep - Physiology - Gamma-Aminobutyric Acid

INTRODUCTION

Approximately 1% of the world’s population suffers from epilepsy[1]. It is a well-known disease even outside the medical field and research realm[2]. Although there is no known cure, many patients control the frequency of their seizures by taking antiepileptic medications[3]. The disease severity can be variable; some patients only occasionally experience a seizure while others have multiple episodes a week. Although it is commonly associated with brief periods of violent convulsions wherein the person loses consciousness, other types of epilepsy manifest differently[4]. Nonetheless, all epileptic seizures share the common characteristic of arising from an overexcitation of neurons in the brain[3],[5]. The pathophysiologic mechanisms leading to a seizure episode consist of synchronous neuronal firing and loss of gamma-aminobutyric acid (GABA)-mediated inhibition[3].

Epileptic seizures have continually been linked to sleep patterns[6]. Specifically, sleep deprivation has been known as a seizure risk in epilepsy patients for many decades[7]-[9]. Neurologists have even utilized this relationship clinically to aid the early diagnosis of epilepsy syndromes[10]-[12]. Aside from its role in inducing seizures, sleep deprivation has many other deleterious effects on people, including impaired cognitive functioning[13]-[15]. GABA-mediated inhibition is involved in promoting sleep. Indeed, the reduced expression of specific GABA receptors has recently been linked to the sleep-deprived state[16]-[18].

Despite recent research studies showing that sleep deprivation can induce seizures, its pathophysiologic mechanisms have not yet been elucidated. This review focuses on the current literature on sleep deprivation as a trigger for epileptic seizures. Additionally, it highlights the need to investigate the possibility that reduced GABA-mediated inhibition could be a mechanism through which sleep deprivation leads to seizures in epileptic patients.

MATERIAL AND METHODS

PubMed was utilized for the literature search. This search was conducted between March 2021 - June 2021. Only articles written in English language were selected. Relevant preclinical and clinical studies were included. The keywords “epilepsy, epidemiology, and seizure types,” when entered in the database, yielded 659 results, of which the most relevant studies were selected. The keywords “sleep physiology and sleep deprivation” and “epilepsy and sleep deprivation” resulted in the retrieval of 8,731 and 551 studies, respectively. Out of these, studies that lay within the scope of this review were selected. Additionally, “epilepsy and GABA-mediated inhibition” and “GABA-mediated inhibition and sleep deprivation” led to 165 and 3 results, respectively, from which pertinent studies were chosen. The methodology is illustrated in [Figure 1].

Figure 1 Flowchart illustrating the methodology. Keywords within the same figure box, for example, epilepsy and sleep deprivation in “PubMed Search 3”, were entered into PubMed together to increase the specificity and relevance of the results.

DISCUSSION

Epilepsy

People are most familiar with tonic-clonic seizures, in which the patient loses consciousness and convulses. However, there are multiple types of epilepsy characterized by different types of seizures[5],[19]. In a broad sense, epilepsy can be divided into the generalized type, in which a seizure attack affects both hemispheres of the brain, and the focal type, in which seizures arise from a specific area. Some focal seizures can also generalize. Since they affect only a particular brain region, focal regions manifest with symptoms indicative of the region. For example, temporal lobe seizures can lead to memory loss[20]. Examples of generalized seizures include absence seizures, which typically affect children, and tonic-clonic seizures[5],[19],[21],[22]. Since all episodes of epilepsy stem from the overexcitation of neurons, this review will collectively refer to epilepsy syndromes in the context of sleep deprivation[3],[5]. An area of potential future research is the investigation of how sleep deprivation affects the seizure threshold in different types of epilepsy.

Studies have shown that epilepsy has adverse effects on mental well-being and quality of life[23]-[25]. Depending on the severity of their epilepsy, patients can feel stigmatized by their condition, and numerous people develop depression[23],[24]. Epilepsy can lead to more sedentary lifestyles because patients fear having seizures in public. This also would adversely affect health outcomes[25].

Not all seizures are caused by epilepsy[26]. For instance, patients with post-traumatic stress disorder can sometimes experience psychogenic seizure disorders, termed psychogenic nonepileptic paroxysms (PNES)[27],[28]. Such patients are often misdiagnosed as having epilepsy, and research is ongoing on how to effectively differentiate between epileptic and psychogenic seizures[29]. However, PNES are not within the scope of this review, which is entirely focused on examining the relationship between epileptic seizures and sleep deprivation.

Sleep physiology and sleep deprivation

Despite sleep being a fundamental physiologic function, its mechanisms are complex[16],[17],[30]-[33]. Therefore, sleep remains an active area of research. Studies have shown that multiple areas of the brain are involved in promoting sleep[16],[30]-[33]. The hypothalamus is a central regulator of the sleep cycle; specifically, the suprachiasmatic nucleus has been revealed to generate circadian rhythms that determine sleep cycles[30],[31]. The brainstem contains a reticular activating system of neurons that is vital in promoting the wakeful state[16],[32]. This system must therefore be inhibited for the sleep state to manifest. Additionally, the thalamus, which acts primarily as a relay center for sensory signals traveling from the periphery, is very active during the awake state and rapid-eye-movement (REM) sleep stages[33]. Finally, GABA, the primary inhibitory neurotransmitter in the central nervous system, has been shown to promote sleep[16],[17],[34],[35].

The sleep cycle can be broadly divided into REM sleep and non-rapid-eye-movement (NREM) sleep[16]-[18],[36],[37]. REM sleep is characterized by less synchronization of neuronal firing and more significant brain activity than NREM sleep[17]. NREM sleep can be further divided into the N1 - 3 stages, in which the waveforms become progressively more synchronized and of higher amplitude on electroencephalogram (EEG)[18]. On the other hand, the waveforms of REM sleep appear similar to those of the awake state such as when the person is actively concentrating[17]. There is also a difference in the types of waves characterizing these two stages of sleep. While REM sleep consists of high frequency, low voltage beta waves, the late- -stage of NREM sleep is characterized by very high amplitude, synchronized delta waves[17],[18]. Due to the higher levels of synchronization in NREM sleep, this stage has been proven to promote epileptic seizures, while REM sleep is a seizure suppressor[38].

A plethora of studies have shown that sleep deprivation has specific detrimental health effects. Cognitive functioning is significantly impaired in sleep-deprived patients[13]-[15]. A meta- analysis revealed that sleep-deprived human subjects displayed decreased mood affect, mental, and motor performance relative to controls[13]. Sleep deprivation also changes EEG waveforms[39],[40]. One study found substantial delta wave activity localized in the frontal and parietal lobes in sleep-deprived patients[40]. Since delta waves are synchronous and constitute a seizure risk in epilepsy, these findings implicate a potential mechanism for sleep deprivation lowering the seizure threshold. Future studies should further explore this and determine whether if this pattern can also be found in other brain regions, such as the temporal lobe. As 35% of adults fail to achieve the recommended seven hours of sleep per night[18], further research into the consequences of sleep deprivation has relevance to patients with and without epilepsy.

Sleep deprivation as a seizure risk in epilepsy

For many years, it has been apparent that sleep deprivation has a relationship to epileptic seizures[6]. In a questionnaire-based study, people with epilepsy commonly reported sleep deprivation as one of the antecedents of their seizures[41]. Conducted in 1998, this research provided a subjective correlation between sleep deprivation and an increased risk of epileptic seizures. Additionally, there is also a wealth of objective evidence for this relationship. Using transcranial magnetic stimulation one study found that sleep deprivation increases cortical excitability in patients with epilepsy[42]. Several other studies have found EEG evidence of increased epileptiform discharges (EDs) in sleepdeprived subjects with epilepsy[8],[9]. In a research study on juvenile myoclonic epilepsy (JME), an idiopathic type of epilepsy that affects children, it was discovered that sleep deprivation increased EDs and paroxysms in such patients[43].

One potential confounder of these study findings is that sleep deprivation could cause the patients to fall asleep during the study, and the increased EDs were related to being in the sleeping state. Previous studies have sought to address this by controlling for the sleeping state[7],[44], demonstrating that sleep deprivation-induced sleep incited more EDs than natural sleep measured on routine EEG[44]. Similarly, more research needs to be done explaining whether sleep deprivation alone induces more EDs than drug-induced sleep in epileptic patients.

Sleep deprivation has been used clinically for years to produce EDs and aid in the diagnosis of epilepsy. Indeed, a 2010 study showed sleep deprivation helps uncover epileptiform activity, aiding in the diagnosis of epilepsy in children[10]. Other studies have demonstrated the application of sleep deprivation in the diagnosis of epilepsy[11],[12]. However, there are discrepancies among the findings of some of these studies. For example, a recent study showcased that sleep deprivation EEG (SD-EEG) was a sensitive diagnostic tool for idiopathic generalized but not focal epilepsy[45]. Conversely, a subsequent empirical evaluation revealed that SD-EEG is an efficacious tool for diagnosing epilepsy[46]. These disparities have been attributed to a wide variance in study methodologies[47]. Future research studies must control for such factors.

Loss of GABA-mediated tonic inhibition as a potential link between sleep deprivation and epilepsy

GABA is critical in maintaining the integrity of the central nervous system through its inhibitory effects[48]. It functions through two different sets of receptors - GABAA and GABAB[34]. When activated, GABAA receptors allow chloride ions to enter the cell, leading to decreased membrane potential and, consequently, neuronal inhibition. These receptors are heteropentameric, consisting of five subunits. Although these subunits are variable, a typical GABAA receptor consists of two alpha (a) subunits, two beta (p) subunits, and a variable fifth subunit, which could be a gamma, delta[6], epsilon, theta, or pie[49],[50].

GABA receptors mediate two different types of inhibition - phasic and tonic[51]. Phasic inhibition is fast-acting and transient in nature. Once the inhibition is over, GABA is removed from the synaptic cleft by uptake into glial cells and presynaptic neurons, where it is catabolized by GABA transaminase[34]. By contrast, tonic inhibition is much longer in duration and is mediated by receptors outside the synapse[50]. This type of inhibition counterbalances the overexcitation of neurons, implicating a role in seizure prevention[34]. Indeed, drugs that facilitate the action of GABA, known as GABA agonists, can help to suppress seizures, while GABA antagonists can precipitate them[52]-[54].

Studies examining human epileptic brain tissue have generally found decreased expression of GABAA receptors[55],[56]. Interestingly, specific subtypes of GABAA receptors, 6-GABAA and a5-GABAA, have garnered the attention of researchers as pertains to epilepsy and sleep deprivation[18],[57]. These receptors are essential for generating tonic inhibition in many brain regions, including the hippocampus and thalamus[58]-[60]. Separate mouse models have discovered the reduced expression of 6-GABAA and a5-GABAA receptors in epilepsy and sleep deprivation, respectively[18],[57]. Such findings suggest that impairment of these GABA receptors in sleep-deprived states could lead to an increased risk of seizures in patients with epilepsy.

CONCLUSION

This paper reviewed the possibility that reduced GABAmediated tonic inhibition could represent the mechanism by which sleep deprivation can lower the seizure threshold. Much of the literature in this field thus far supports a direct correlation between sleep deprivation and seizure risk in epilepsy. In addition, numerous studies have emphasized the diagnostic importance of clinically induced sleep deprivation. Despite these advancements, more mechanistic clinical studies remain to be done. Encouragingly, murine studies have shown lower 6-GABAA and a5-GABAA receptor expression in both epilepsy and sleep deprivation. Researchers will need to determine if these findings can be extrapolated to humans.

Additionally, these preclinical studies have investigated GABA receptor expression in sleep deprivation and epilepsy separately, but not in the same experimental setting. Future studies could, for instance, explore how reduced expression of 6-GABAA and a5-GABAA receptors in the sleep-deprived state contributes to a higher risk of seizures in people with epilepsy. Before this interplay can be addressed experimentally, however, more research needs to document and confirm the finding that 6-GABAA and a5-GABAA receptors have lower expression in sleep-deprived humans.

Sleep deprivation leading to an increased risk of epileptic seizures remains an underexplored area of research. This review addressed the paucity of mechanistic and explanatory findings by highlighting existing preclinical and clinical studies. Even if it turns out that reduced GABA-mediated inhibition is not the only factor contributing to sleep deprivation-induced seizures, elucidating this mechanism is imperative to better understand epileptogenesis, which would lead to more efficacious treatment for epilepsy.

Conflict of Interests

The authors have no conflict of interests to declare.

Declaration

The authors did not receive any funding and report no conflicts of interest in this work.

• REFERENCES

• 1 Thijs RD, Surges R, O’Brien TJ, Sander JW. Epilepsy in adults. Lancet (Lond). 2019 Feb;393(10172):689-701.
• 2 Herrmann LK, Welter E, Berg AT, Perzynski AT, Van Doren JR, Sajatovic M. Epilepsy misconceptions and stigma reduction: current status in western countries. Epilepsy Behav. 2016 Jul;60:165-73.
• 3 Giourou E, Stavropoulou-Deli A, Giannakopoulou A, Kostopoulos GK, Koutroumanidis M. Introduction to Epilepsy and Related Brain Disorders. In: Voros NS, Antonopoulos CP, eds. Cyberphysical systems for epilepsy and related brain disorders: multiparametric monitoring and analysis for diagnosis and optimal disease management. Cham: Springer International Publishing; 2015. p. 11-38.
• 4 Pack AM. Epilepsy overview and revised classification of seizures and epilepsies. Continuum (Minneap Minn). 2019 Apr;25(2):306-21.
• 5 Anwar H, Khan QU, Nadeem N, Pervaiz I, Ali M, Cheema FF. Epileptic seizures. Discov (Craiova). 2020 Jun;8(2):e110.
• 6 Wang YQ, Zhang MQ, Li R, Qu WM, Huang ZL. The mutual interaction between sleep and epilepsy on the neurobiological basis and therapy. Curr Neuropharmacol. 2018 Jan;16(1):5-16.
• 7 Malow BA. Sleep deprivation and epilepsy. Epilepsy Curr. 2004 Sep;4(5):193-5.
• 8 Mattson RH, Pratt KL, Calverley JR. Electroencephalograms of epileptics following sleep deprivation. Arch Neurol. 1965 Sep;13(3):310-5.
• 9 Pratt KL, Mattson RH, Weikers NJ, Williams R. EEG activation of epileptics following sleep deprivation: a prospective study of 114 cases. Electroencephalogr Clin Neurophysiol. 1968 Jan;24(1):11-5.
• 10 Shahar E, Genizi J, Ravid S, Schif A. The complementary value of sleep-deprived EEG in childhood onset epilepsy. Eur J Paediatr Neurol. 2010 Jul;14(4):308-12.
• 11 Kubicki S, Scheuler W, Wittenbecher H. Short-term sleep EEG recordings after partial sleep deprivation as a routine procedure in order to uncover epileptic phenomena: an evaluation of 719 EEG recordings. Epilepsy Res Suppl. 1991;2:217-30.
• 12 Liporace J, Tatum W 4th, Morris GL 3rd, French J. Clinical utility of sleep-deprived versus computer-assisted ambulatory 16-channel EEG in epilepsy patients: a multi-center study. Epilepsy Res. 1998 Nov;32(3):357-62.
• 13 Pilcher JJ, Huffcutt AI. Effects of sleep deprivation on performance: a meta-analysis. Sleep. 1996 May;19(4):318-26.
• 14 Van Dongen HPA, Maislin G, Mullington JM, Dinges DF. The cumulative cost of additional wakefulness: dose-response effects on neurobehavioral functions and sleep physiology from chronic sleep restriction and total sleep deprivation. Sleep. 2003 Mar;26(2):117-26.
• 15 Kusztor A, Raud L, Juel BE, Nilsen AS, Storm JF, Huster RJ. Sleep deprivation differentially affects subcomponents of cognitive control. Sleep. 2019 Apr;42(4):zsz016.
• 16 Bishir M, Bhat A, Essa MM, Ekpo O, Ihunwo AO, Veeraraghavan VP, et al. Sleep deprivation and neurological disorders. Biomed Res Int. 2020;2020:5764017.
• 17 Eban-Rothschild A, Appelbaum L, Lecea L. Neuronal mechanisms for sleep/wake regulation and modulatory drive. Neuropsychopharmacology. 2018 Apr;43(5):937-52.
• 18 Reddy DS, Chuang SH, Hunn D, Crepeau AZ, Maganti R. Neuroendocrine aspects of improving sleep in epilepsy. Epilepsy Res. 2018 Nov;147:32-41.
• 19 Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, Van Emde Boas W, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia. 2010 Apr;51(4):676-85.
• 20 Postma TS, Cury C, Baxendale S, Thompson PJ, Cano-Lopez I, Tisi J, et al. Hippocampal shape is associated with memory deficits in temporal lobe epilepsy. Ann Neurol. 2020 Jul;88(1):170-82.
• 21 Panayiotopoulos CP, Obeid T, Waheed G. Differentiation of typical absence seizures in epileptic syndromes. A video EEG study of 224 seizures in 20 patients. Brain. 1989 Aug;112(Pt 4):1039-56.
• 22 Koutroumanidis M, Bruno E. Epileptology of the first tonic-clonic seizure in adults and prediction of seizure recurrence. Epileptic Disord. 2018 Dec;20(6):490-501.
• 23 Yeni K, Tulek Z, Simsek OF, Bebek N. Relationships between knowledge, attitudes, stigma, anxiety and depression, and quality of life in epilepsy: a structural equation modeling. Epilepsy Behav. 2018 Aug;85:212-7.
• 24 Jacoby A, Austin JK. Social stigma for adults and children with epilepsy. Epilepsia. 2007;48(Suppl 9):6-9.
• 25 Tedrus GMAS, Sterca GS, Pereira RB. Physical activity, stigma, and quality of life in patients with epilepsy. Epilepsy Behav. 2017 Dec;77:96-8.
• 26 Dericioglu N, Saygi S, Ciger A. The value of provocation methods in patients suspected of having non-epileptic seizures. Seizure. 1999 May;8(3):152-6.
• 27 Devinsky O, Gazzola D, LaFrance WCJ. Differentiating between nonepileptic and epileptic seizures. Nat Rev Neurol. 2011 Apr;7(4):210-20.
• 28 Vanek J, Prasko J, Ociskova M, Genzor S, Holubova M, Hodny F, et al. Sleep disturbances in patients with nonepileptic seizures. Nat Sci Sleep. 2021;13:209-18.
• 29 Wang AD, Leong M, Johnstone B, Rayner G, Kalincik T, Roos I, et al. Distinct psychopathology profiles in patients with epileptic seizures compared to non-epileptic psychogenic seizures. Epilepsy Res. 2019 Dec;158:106234.
• 30 Hastings MH, Maywood ES, Brancaccio M. Generation of circadian rhythms in the suprachiasmatic nucleus. Nat Rev Neurosci. 2018 Aug;19(8):453-69.
• 31 Brancaccio M, Patton AP, Chesham JE, Maywood ES, Hastings MH. Astrocytes control circadian timekeeping in the suprachiasmatic nucleus via glutamatergic signaling. Neuron [Internet]. 2017 Mar; [cited 2017 Mar 09]; 93(6):1420-35.e5. Available from: https://pubmed.ncbi. nlm.nih.gov/28285822
• 32 Yeo SS, Chang PH, Jang SH. The ascending reticular activating system from pontine reticular formation to the thalamus in the human brain. Front Hum Neurosci. 2013;7:416.
• 33 Gent TC, Bandarabadi M, Herrera CG, Adamantidis AR. Thalamic dual control of sleep and wakefulness. Nat Neurosci. 2018 Jul;21(7):974-84.
• 34 Treiman DM. GABAergic mechanisms in epilepsy. Epilepsia. 2001;42(Suppl 3):8-12.
• 35 Schwartz RD. The GABAA receptor-gated ion channel: biochemical and pharmacological studies of structure and function. Biochem Pharmacol. 1988 Sep;37(18):3369-75.
• 36 Lanigar S, Bandyopadhyay S. Sleep and epilepsy: a complex interplay. Mo Med. 2017 Nov/Dec;114(6):453-7.
• 37 Foldvary-Schaefer N, Grigg-Damberger M. Sleep and epilepsy. Semin Neurol. 2009 Sep;29(4):419-28.
• 38 Tseng HT, Hsiao YT, Yi PL, Chang FC. Deep brain stimulation increases seizure threshold by altering REM sleep and delta powers during NREM Sleep. Front Neurol. 2020 Aug;11:752.
• 39 Zhang J, Lau EYY, Hsiao JH. Sleep deprivation compromises restingstate emotional regulatory processes: an EEG study. J Sleep Res. 2019 Jun;28(3):e12671.
• 40 Bersagliere A, Pascual-Marqui RD, Tarokh L, Achermann P. Mapping slow waves by EEG topography and source localization: effects of sleep deprivation. Brain Topogr. 2018 Mar;31(2):257-69.
• 41 Spatt J, Langbauer G, Mamoli B. Subjective perception of seizure precipitants: results of a questionnaire study. Seizure. 1998 Oct;7(5):391-5.
• 42 Badawy RAB, Curatolo JM, Newton M, Berkovic SF, Macdonell RAL. Sleep deprivation increases cortical excitability in epilepsy: syndromespecific effects. Neurology. 2006 Sep;67(6):1018-22.
• 43 Sousa NAC, Sousa PS, Garzon E, Sakamoto AC, Braga NIO, Yacubian EMT. EEG recording after sleep deprivation in a series of patients with juvenile myoclonic epilepsy. Arq Neuropsiquiatr. 2005 Jun;63(2B):383-8.
• 44 Fountain NB, Kim JS, Lee SI. Sleep deprivation activates epileptiform discharges independent of the activating effects of sleep. J Clin Neurophysiol. 1998 Jan;15(1):69-75.
• 45 Renzel R, Baumann CR, Poryazova R. EEG after sleep deprivation is a sensitive tool in the first diagnosis of idiopathic generalized but not focal epilepsy. Clin Neurophysiol. 2016 Jan;127(1):209-13.
• 46 Colon AJ, Ronner HE, Boon P, Ossenblok P. Evaluation of MEG vs EEG after sleep deprivation in epilepsy. Acta Neurol Scand. 2017 Feb;135(2):247-51.
• 47 Giorgi FS, Guida M, Caciagli L, Maestri M, Carnicelli L, Bonanni E, et al. What is the role for EEG after sleep deprivation in the diagnosis of epilepsy? Issues, controversies, and future directions. Neurosci Biobehav Rev. 2014 Nov;47:533-48.
• 48 Roth FC, Draguhn A. GABA metabolism and transport: effects on synaptic efficacy. Neural Plast. 2012;2012:805830.
• 49 Sieghart W, Sperk G. Subunit composition, distribution and function of GABA(A) receptor subtypes. Curr Top Med Chem. 2002 Aug;2(8):795-816.
• 50 Lee V, Maguire J. The impact of tonic GABAA receptor-mediated inhibition on neuronal excitability varies across brain region and cell type. Front Neural Circuits. 2014;8:3.
• 51 Farrant M, Nusser Z. Variations on an inhibitory theme: phasic and tonic activation of GABA(A) receptors. Nat Rev Neurosci. 2005 Mar;6(3):215-29.
• 52 Dalby NO. GABA-level increasing and anticonvulsant effects of three different GABA uptake inhibitors. Neuropharmacology. 2000 Sep;39(12):2399-407.
• 53 Sato K, Morimoto K, Okamoto M, Nakamura Y, Otsuki S, Sato M. An analysis of anticonvulsant actions of GABA agonists (progabide and baclofen) in the kindling model of epilepsy. Epilepsy Res. 1990 Mar;5(2):117-24.
• 54 Puri MM, Kumar L, Vishwakarma PD, Behera D. Seizures with single therapeutic dose of isoniazid. Indian J Tuberc. 2012 Apr;59(2):100-2.
• 55 McDonald JW, Garofalo EA, Hood T, Sackellares JC, Gilman S, McKeever PE, et al. Altered excitatory and inhibitory amino acid receptor binding in hippocampus of patients with temporal lobe epilepsy. Ann Neurol. 1991 May;29(5):529-41.
• 56 Loup F, Wieser HG, Yonekawa Y, Aguzzi A, Fritschy JM. Selective alterations in GABAA receptor subtypes in human temporal lobe epilepsy. J Neurosci. 2000 Jul;20(14):5401-19.
• 57 Peng Z, Huang CS, Stell BM, Mody I, Houser CR. Altered expression of the delta subunit of the GABAA receptor in a mouse model of temporal lobe epilepsy. J Neurosci. 2004 Sep;24(39):8629-39.
• 58 Brickley SG, Mody I. Extrasynaptic GABA(A) receptors: their function in the CNS and implications for disease. Neuron. 2012 Jan;73(1):23-34.
• 59 Glykys J, Mann EO, Mody I. Which GABA(A) receptor subunits are necessary for tonic inhibition in the hippocampus? J Neurosci. 2008 Feb;28(6):1421-6.
• 60 Herd MB, Foister N, Chandra D, Peden DR, Homanics GE, Brown VJ, et al. Inhibition of thalamic excitability by 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-3-ol: a selective role for delta-GABA(A) receptors. Eur J Neurosci. 2009 Mar;29(6):1177-87.

Publication History

Received: 02 July 2021

Accepted: 15 October 2021

Article published online:
01 December 2023