title: Regulation of epileptiform activity by two distinct subtypes of extrasynaptic GABAA receptors.
abstract: BACKGROUND
  GABAergic deficit is one of the major mechanisms underlying epileptic seizures. Previous studies have mainly focused on alterations of synaptic GABAergic inhibition during epileptogenesis. Recent work suggested that tonic inhibition may also play a role in regulating epileptogenesis, but the underlying mechanism is not well understood.
  
  
  RESULTS
  We employed molecular and pharmacological tools to investigate the role of tonic inhibition during epileptogenesis both in vitro and in vivo. We overexpressed two distinct subtypes of extrasynaptic GABAA receptors, α5β3γ2 and α6β3δ receptors, in cultured hippocampal neurons. We demonstrated that overexpression of both α5β3γ2 and α6β3δ receptors enhanced tonic inhibition and reduced epileptiform activity in vitro. We then showed that injection of THIP (5 μM), a selective agonist for extrasynaptic GABAA receptors at low concentration, into rat brain also suppressed epileptiform burst activity and behavioral seizures in vivo. Mechanistically, we discovered that low concentration of THIP had no effect on GABAergic synaptic transmission and did not affect the basal level of action potentials, but significantly inhibited high frequency neuronal activity induced by epileptogenic agents.
  
  
  CONCLUSIONS
  Our studies suggest that extrasynaptic GABAA receptors play an important role in controlling hyperexcitatory activity, such as that during epileptogenesis, but a less prominent role in modulating a low level of basal activity. We propose that tonic inhibition may play a greater role under pathological conditions than in physiological conditions in terms of modulating neural network activity.
authors: Institutes of Brain Science and State Key Laboratory for Medical Neurobiology, Fudan University, Shanghai, 200032, China.
authors: Yajie
authors: Y
authors: Sun
authors: Zheng
authors: Z
authors: Wu
authors: Shuzhen
authors: S
authors: Kong
authors: Dongyun
authors: D
authors: Jiang
authors: Anar
authors: A
authors: Pitre
authors: Yun
authors: Y
authors: Wang
authors: Gong
authors: G
authors: Chen
mesh_terms: D000818:Animals; D001581:Benzothiadiazines / Q000494:pharmacology; D002478:Cells, Cultured; D004827:Epilepsy / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D057809:HEK293 Cells; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D015640:Ion Channel Gating / Q000187:drug effects; D007555:Isoxazoles / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D012640:Seizures / Q000378:metabolism / Q000503:physiopathology; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D001581:Benzothiadiazines; D007555:Isoxazoles; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; C015542:gaboxadol; C004639:cyclothiazide
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