title: Dual mechanisms diminishing tonic GABAA inhibition of dentate gyrus granule cells in Noda epileptic rats.
abstract: The Noda epileptic rat (NER), a Wistar colony mutant, spontaneously has tonic-clonic convulsions with paroxysmal discharges. In the present study, we measured phasic and tonic γ-aminobutyric acid A (GABAA) current (I tonic) in NER hippocampal dentate gyrus granule cells and compared the results with those of normal parent strain Wistar rats (WIS). I tonic, revealed by a bicuculline-induced outward shift in holding current, was significantly smaller in NER than in WIS (P < 0.01). The frequency of inhibitory postsynaptic currents (IPSCs) was also significantly lower in NER than in WIS (P < 0.05), without significant differences in the IPSC amplitude or decay time between WIS and NER. I tonic attenuation in NER was further confirmed in the presence of GABA transporter blockers, NO-711 and nipecotic acid, with no difference in neuronal GABA transporter expression between WIS and NER. I tonic responses to extrasynaptic GABAA receptor agonists (THIP and DS-2) were significantly reduced in NER compared with WIS (P < 0.05). Allopregnanolone caused less I tonic increase in NER than in WIS, while it prolonged the IPSC decay time to a similar rate in the two groups. Expression of the GABAA receptor δ-subunit was decreased in the dentate gyrus of NER relative to that of WIS. Taken together, our results showed that a combination of attenuated presynaptic GABA release and extrasynaptic GABAA receptor expression reduced I tonic amplitude and its sensitivity to neurosteroids, which likely diminishes the gating function of dentate gyrus granule cells and renders NER more susceptible to seizure propagation.
authors.affiliation: Department of Physiology, School of Medicine and Brain Research Institute, Chungnam National University, Daejeon, South Korea.
authors.forename: Sudip
authors.initials: S
authors.lastname: Pandit
authors.forename: Ji Ae
authors.initials: JA
authors.lastname: Jeong
authors.forename: Ji Yoon
authors.initials: JY
authors.lastname: Jo
authors.forename: Hyun Sill
authors.initials: HS
authors.lastname: Cho
authors.forename: Dong Woon
authors.initials: DW
authors.lastname: Kim
authors.forename: Jae Moon
authors.initials: JM
authors.lastname: Kim
authors.forename: Pan Dong
authors.initials: PD
authors.lastname: Ryu
authors.forename: So Yeong
authors.initials: SY
authors.lastname: Lee
authors.forename: Hyun Woo
authors.initials: HW
authors.lastname: Kim
authors.forename: Byeong Hwa
authors.initials: BH
authors.lastname: Jeon
authors.forename: Jin Bong
authors.initials: JB
authors.lastname: Park
mesh_terms: D000818:Animals; D018891:Dentate Gyrus / Q000503:physiopathology*; D004830:Epilepsy, Tonic-Clonic / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D009433:Neural Inhibition / Q000502:physiology*; D051381:Rats; D011922:Rats, Mutant Strains; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000502:physiology*
chemical_list: D011963:Receptors, GABA-A
keywords: GABAA receptors; Noda epileptic rat; dentate gyrus granule cells