title: In vivo electroretinographic studies of the role of GABAC receptors in retinal signal processing.
abstract: All three classes of receptors for the inhibitory neurotransmitter GABA (GABAR) are expressed in the retina. This study investigated roles of GABAR, especially GABACR (GABA(A)-ρ), in retinal signaling in vivo by studying effects on the mouse electroretinogram (ERG) of genetic deletion of GABACR versus pharmacological blockade using receptor antagonists. Brief full-field flash ERGs were recorded from anesthetized GABACR(-/-) mice, and WT C57BL/6 (B6) mice, before and after intravitreal injection of GABACR antagonists, TPMPA, 3-APMPA, or the more recently developed 2-AEMP; GABAAR antagonist, SR95531; GABABR antagonist, CGP, and agonist, baclofen. Intravitreal injections of TPMPA and SR95531 were also made in Brown Norway rats. The effect of 2-AEMP on GABA-induced current was tested directly in isolated rat rod bipolar cells, and 2-AEMP was found to preferentially block GABACR in those cells. Maximum amplitudes of dark (DA) and light-adapted (LA) ERG b-waves were reduced in GABACR(-/-) mice, compared to B6 mice, by 30-60%; a-waves were unaltered and oscillatory potential amplitudes were increased. In B6 mice, after injection of TPMPA (also in rats), 3-APMPA or 2-AEMP, ERGs became similar to ERGs of GABACR(-/-) mice. Blockade of GABAARs and GABABRs, or agonism of GABABRs did not alter B6 DA b-wave amplitude. The negative scotopic threshold response (nSTR) was slightly less sensitive in GABACR(-/-) than in B6 mice, and unaltered by 2-AEMP. However, amplitudes of nSTR and photopic negative response (PhNR), both of which originate from inner retina, were enhanced by TPMPA and 3-APMPA, each of which has GABAB agonist properties, and further increased by baclofen. The finding that genetic deletion of GABACR, the GABACR antagonist 2-AEMP, and other antagonists all reduced ERG b-wave amplitude, supports a role for GABACR in determining the maximum response amplitude of bipolar cells contributing to the b-wave. GABACR antagonists differed in their effects on nSTR and PhNR; antagonists with GABAB agonist properties enhanced light-driven responses whereas 2-AEMP did not.
authors.affiliation: College of Optometry, University of Houston, Houston, TX 77204, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: College of Optometry, University of Houston, Houston, TX 77204, USA; Department of Neurology, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
authors.forename: Deb Kumar
authors.initials: DK
authors.lastname: Mojumder
authors.affiliation: Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN 37831, USA; Chengdu Kanghong Pharmaceutical Co., Ltd., Sichuan, People's Republic of China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yan
authors.affiliation: Lions of Illinois Eye Research Institute, Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, University of Illinois at Chicago, Chicago, IL 60612, USA; Lifespan Cardiovascular Institute and the Warren Alpert School of Medicine of Brown University, Providence, RI 02906, USA.
authors.forename: An
authors.initials: A
authors.lastname: Xie
authors.affiliation: Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN 37831, USA; Department of Biochemistry and Molecular & Cellular Biology, University of Tennessee, Knoxville, TN 37996, USA.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Standaert
authors.affiliation: Lions of Illinois Eye Research Institute, Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, University of Illinois at Chicago, Chicago, IL 60612, USA; National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Haohua
authors.initials: H
authors.lastname: Qian
authors.affiliation: Lions of Illinois Eye Research Institute, Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Pepperberg
authors.affiliation: College of Optometry, University of Houston, Houston, TX 77204, USA.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Frishman
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004247:DNA / Q000235:genetics*; D004195:Disease Models, Animal; D004596:Electroretinography; D005260:Female; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA / Q000096:biosynthesis / Q000235:genetics*; D012160:Retina / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D012164:Retinal Diseases / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology
chemical_list: C087200:GABA-C receptor; D018079:Receptors, GABA; D004247:DNA
keywords: Electroretinogram; GABA; GABA receptors; Retina; Retinal signaling