title: Blocking GABA(C) receptors increases light responsiveness of retinal ganglion cells in a rat model of retinitis pigmentosa.
abstract: Previous studies in a mouse model of retinitis pigmentosa indicate that the GABAergic system in the retina may be overactive. GABA is known to act on GABA(C) receptors present on the axon terminals of bipolar cells to inhibit the release of excitatory neurotransmitter from these cells. The present study examined the effects of a GABA(C) receptor antagonist on the light-evoked responses of retinal ganglion cells (RGCs) in a rat model of retinitis pigmentosa. Extracellular recordings were made from RGCs in retinas isolated from P23H transgenic rats and non-dystrophic Sprague-Dawley (SD) rats. Spike activity of RGCs was measured in response to brief flashes of light over a range of light intensities. Intensity-response curves were evaluated prior to and during bath application of the GABA(C) receptor antagonist TPMPA. I found that TPMPA consistently increased the sensitivity of P23H rat RGCs to light flashes. For ON-center RGCs (n = 21), the average increase in light sensitivity was 0.63 log unit. For OFF-center RGCs (n = 6), the average increase was 0.38 log unit. TPMPA increased the maximum peak response of ON-center RGCs by 22% and OFF-center RGCs by 11%. However, the increase in maximum peak response of OFF-center RGCs was not statistically significant. TPMPA had no significant effect on the dynamic operating range of either ON-center or OFF-center RGCs. Nine ON-center SD rat RGCs were also tested. In contrast to what was observed for P23H rat RGCs, TPMPA decreased the sensitivity of these RGCs to light flashes, on average by 0.20 log unit. In conclusion, GABA(C) receptors may be novel targets for therapeutic interventions aimed at increasing light responsiveness in patients with retinitis pigmentosa or other diseases involving degeneration of photoreceptors.
authors.affiliation: VA Boston Healthcare System, Mail Stop 151E, 150 South Huntington Avenue, Boston, MA 02130, USA. Ralph.jensen@va.gov
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: Jensen
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D004195:Disease Models, Animal; D004594:Electrophysiology; D018756:GABA Antagonists / Q000494:pharmacology*; D008027:Light; D010721:Phosphinic Acids / Q000494:pharmacology*; D010775:Photic Stimulation; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D018079:Receptors, GABA / Q000378:metabolism*; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000502:physiology*; D012174:Retinitis Pigmentosa / Q000378:metabolism / Q000517:prevention & control*; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: C101879:(1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid; D018756:GABA Antagonists; C087200:GABA-C receptor; D010721:Phosphinic Acids; D011725:Pyridines; D018079:Receptors, GABA