Modeling of electroretinography b-wave amplitudes validates a critical role of tonic GABA_C receptor-carried chloride currents in sensitizing and light adapting rod bipolar cell light responses

Abstract

Purpose: Our recent work (Herrmann et al., Neuron, 2011, 72(1):101-10) demonstrated that the light sensitivity and operational range of rod bipolar cells are regulated by a tonic GABAergic input, which evokes sustained GABA_C receptor-carried chloride currents. Our data predict that this chloride current makes a major contribution to hyperpolarizing rod bipolar cells both in the dark and in the presence of background illumination, thereby increasing the amplitudes of their depolarizing light responses and extending their operational range. The goal of this study was to develop a theoretical model describing the properties of these sustained chloride currents.

Methods: To validate our model, we performed global least-square fitting of the rod bipolar cell stimulus-response plots obtained from electroretinography (ERG) b-wave recordings of wild type and GABA_C receptor knockout mice, and of wild type mice after intraocular injection of GABA, respectively. We fitted the model equations to ERG flash response families recorded under different intensities of steady background illumination.

Results: Our analysis demonstrates that the presence of sustained GABA_C receptor-mediated chloride currents is necessary and sufficient to explain the observed difference in the amplitudes and operational ranges of wild type mice with and without GABA injections, and GABA_C receptor knockout mice, respectively. Furthermore, our model makes the following major predictions: 1) The reversal potential for potassium is more positive than the reversal potential for chloride, which presumes the presence of a large chloride gradient across the cell membrane. 2) In rod bipolar cells lacking the GABA_C receptor, the sustained chloride current is abolished, indicating that this current is carried exclusively by the GABA_C receptor. 3) The chloride conductance is light-dependent and increases with increasing background illumination.

Conclusions: Our results indicate that the rod bipolar cell functions as an atypical neuron which employs not only potassium but also chloride currents for hyperpolarization of the resting potential. The chloride conductance can be regulated by inputs from other GABAergic retinal neurons and, therefore, serves as a mechanism that adjusts rod bipolar cell light responses to changes in background illumination.

Keywords: 435 bipolar cells • 688 retina • 473 computational modeling