Seizures affect almost 3 million peoples in US and in two thirds of patients, the causes are not known (possible genetic origins). Idiopathic generalized epilepsy(IGE) has been recognized as its genetic origins which include many single-nucleotide polymorphisms (SNPs) or mutation of ionotropic receptors, such as GABAergic receptor (GABAR) subunit mutations (Gabrg2Q390X and Gabra1A322D) linked to severe Dravet epilepsy syndrome and child absence epilepsy, and cognitive comorbidity in patients. In contrast to acquired seizures study, IGE seizure and epileptogenesis mechanism remains largely elusive. Moreover, seizures and sleep influence/interact with each other in their physiology mechanism, which imposes a challenge to IGE study and patient treatment. In one recent human patient study, sleep-like slow-wave oscillation has been shown to facilitate epileptic seizure activity. Therefore, we hypothesize that sleep-related slow-wave hyperpolarization-depolarization oscillation(SWO) can drive homeostatic potentiation(HSP) of excitatory synaptic currents, not inhibitory synaptic currents in cortical neurons of thalamocortical circuitry in IGE animal models with Gabrg2Q390X or Gabra1A322D mutation, and therefore create an escaped excitatory synaptic currents (without balancing from inhibitory synaptic currents) in cortical neurons during sleep and sleep-wake transition. This critical step of gabaergic current HSP impairment induced by SWOs can lead to seizure occurrence/initiation and also contribute to epileptogenesis in IGE models. This work will fill a critical void in our understanding of seizure mechanism, plus epileptogenesis, and potentially generate a new seizure therapy. First, we will study whether SWO-induced HSP of inhibitory GABAR-mediated currents is impaired, but not excitatory AMPAR-mediated currents in layer V-VI cortical neurons in vitro from heterozygous Gabrg2+/Q390X or Gabra1+/A322D knock-in mice and whether this impairment results in neuronal elevated firing. Second, we will determine whether light-induced SWOs in vivo causally initiate epileptic activity in cortex from mice expressing halorhodopsin (NpHR) and Gabrg2Q390X or Gabra1A322D mutation. Last, we will use a retinoid acid synthesis blocker DEAB to maintain the dynamic HSP balance between synaptic excitatory and inhibitory currents during SWOs in IGE models, which will provide a proof of principle for a potential seizure therapy. The information generated in these studies will substantially alter our view of seizure/epileptogenesis regarding its interaction with sleep waves and eventually lead to a new seizure therapy in IGE patients.

Public Health Relevance

Seizures are severe syndrome influencing almost 3 million people in US. Most seizures are caused by gene mutation and their seizure mechanisms remain unknown. This proposal will clarify seizure mechanisms being entangled with sleep and generate a potential new treatment of seizures.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Acute Neural Injury and Epilepsy Study Section (ANIE)
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Whittemore, Vicky R
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Vanderbilt University Medical Center
Schools of Medicine
United States
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Huang, Xuan; Zhou, Chengwen; Tian, Mengnan et al. (2017) Overexpressing wild-type ?2 subunits rescued the seizure phenotype in Gabrg2+/Q390X Dravet syndrome mice. Epilepsia 58:1451-1461