Blocking mGluR1 receptors but not GABA_A receptors increases light responsiveness of retinal ganglion cells in a rat model of retinitis pigmentosa

Abstract

Purpose: Transmitter release from the axon terminals of retinal bipolar cells is modulated by GABA acting on GABA_A and GABA_C receptors. Recently I reported (Exp. Eye Res. 2012) that the GABA_C receptor antagonist TPMPA increases both light sensitivity and maximum peak response of most retinal ganglion cells (RGCs) in the P23H rat. Here, I examined whether a similar effect could occur with a GABA_A receptor antagonist or a metabotropic glutamate receptor type 1 (mGluR1) antagonist, which is thought to inhibit GABA release onto bipolar cells.

Methods: Extracellular recordings were made from P23H rat RGCs in the isolated retina. The responses (spike activity) of these cells to flashes of light were recorded and intensity-response curves were constructed. Receptor antagonists were bath applied.

Results: The mGluR1 antagonist JNJ16259685 (0.5 µM) increased light sensitivity of all ON-center RGCs (n = 20) examined and 7 of 9 OFF-center RGCs examined. For ON-center cells, light sensitivity increased on average by 0.58 log unit. For OFF-center cells, light sensitivity increased on average by 0.12 log unit. JNJ16259685 increased the maximum peak response of 13 of the 20 ON-center RGCs to a high intensity light stimulus. On average (n = 20) the maximum peak response increased by 7%. For OFF-center cells (n = 9), JNJ16259685 had no statistically significant on the maximum peak response. JNJ16259685 also had no statistically significant effect on the dynamic operating range of either ON-center or OFF-center RGCs. The effect of the GABA_A receptor antagonist SR95531 (5 µM) on the light responsiveness of 9 ON-center RGCs was examined. On average SR95531 decreased the maximum peak response of the RGCs by 18%. No statistically significant effect was found on either the light sensitivity or dynamic operating range of the RGCs.

Conclusions: The mGluR1 antagonist JNJ16259685 increases light responsiveness of most P23H rat RGCs. The greatest effect was on ON-center RGCs, similar to that found previously with the GABA_C receptor antagonist TPMPA.

Keywords: 531 ganglion cells • 691 retina: proximal (bipolar, amacrine, and ganglion cells) • 696 retinal degenerations: hereditary