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Title: In vivo electroretinographic studies of the role of GABA C receptors in retinal signal processing

The retina expresses all three classes of receptors for the inhibitory neurotransmitter GABA (GABAR). Our study investigated roles of GABAR, especially GABA(C)R (GABA(A)-rho), in retinal signaling in vivo by studying effects on the mouse electroretinogram (ERG) of genetic deletion of GABA(C)R versus pharmacological blockade using receptor antagonists. Brief full-field flash ERGs were recorded from anesthetized GABA(C)R(-/-) mice, and WT C57BL/6 (B6) mice, before and after intravitreal injection of GABA(C)R antagonists, TPMPA, 3-APMPA, or the more recently developed 2-AEMP; GABA(A)R antagonist, SR95531; GABA(B)R 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 GABA(C)R in those cells. Maximum amplitudes of dark (DA) and light-adapted (LA) ERG b-waves were reduced in GABA(C)R(-/-) 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 GABA(C)R(-/-) mice. Blockade of GABA(A)Rs and GABA(B)Rs, or agonism of GABA(B)Rs did not alter B6 DA b-wave amplitude. Furthermore, the negative scotopic threshold responsemore » (nSTR) was slightly less sensitive in GABA(C)R(-/-) 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 GABA(B) agonist properties, and further increased by baclofen. The finding that genetic deletion of GABA(C)R, the GABA(C)R antagonist 2-AEMP, and other antagonists all reduced ERG b-wave amplitude, supports a role for CABA(C)R in determining the maximum response amplitude of bipolar cells contributing to the b-wave. GABA(C)R antagonists differed in their effects on nSTR and PhNR; antagonists with GABA(B) agonist properties enhanced light-driven responses whereas 2-AEMP did not.« less
Authors:
 [1] ;  [2] ;  [3] ;  [4] ;  [5] ;  [6] ;  [7] ; ORCiD logo [1]
  1. Univ. of Houston, TX (United States). College of Optometry
  2. Univ. of Houston, TX (United States). College of Optometry; Texas Tech Univ., Lubbock, TX (United States). Dept. of Neurobiology
  3. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Biosciences Division; Chengdu Kanghong Pharmaceutical Co., Sichuan (People's Republic of China)
  4. Univ. of Illinois, Chicago, IL (United States). Lions of Illinois Eye Research Inst.; Brown Univ., Providence, RI (United States). Lifespan Cardiovascular Inst. and Warren Alpert School of Medicine
  5. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Biosciences Division; Univ. of Tennessee, Knoxville, TN (United States). Dept. of Biochemistry and Molecular and Cellular Biology
  6. Univ. of Illinois, Chicago, IL (United States). Lions of Illinois Eye Research Inst.; National Inst. of Health (NIH), Bethesda, MD (United States). National Eye Inst.
  7. Univ. of Illinois, Chicago, IL (United States). Lions of Illinois Eye Research Inst.
Publication Date:
Grant/Contract Number:
AC05-00OR22725
Type:
Accepted Manuscript
Journal Name:
Experimental Eye Research
Additional Journal Information:
Journal Volume: 139; Journal Issue: C; Journal ID: ISSN 0014-4835
Publisher:
Elsevier
Research Org:
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Electroretinogram; GABA; GABA receptors; Retina; Retinal signaling; DARK-ADAPTED ELECTRORETINOGRAM; ROD BIPOLAR CELLS; SCOTOPIC THRESHOLD RESPONSE; GAMMA-AMINOBUTYRIC-ACID; MOUSE RETINA; CAT RETINA; RAT RETINA; B-WAVE; HORIZONTAL CELLS; TRANSMITTER RELEASE
OSTI Identifier:
1334449