Postsynaptic mechanisms of adaptation at the first retinal synapse

Abstract

The retina can distinguish light spanning more than 10 log units of intensity, an enormous dynamic range. To accomplish this, the cells of the retina must compress the visual signal into a more manageable 2-3 log unit range by changing their sensitivity depending on light condition. Some of these adaptive mechanisms originate in the photoreceptor, but there is strong evidence that most are downstream from photoreceptors, beginning with the On bipolar cell, which is the first stop for visual information on the way to the brain. In this thesis, I present evidence for two mechanisms mediating adaptation at the On bipolar cell level. In chapter 2, I discuss a negative feedback circuit, which acts to restore the response range of the On bipolar cell during conditions of high illumination. This process is local, and involves activation of calcineurin by calcium influx through the mGluR6 gated transduction channel. Our data suggest that Ca2+ and calcineurin may play an adaptive role at the synapse between photoreceptor and On bipolar cells, closing postsynaptic cation channels that are opened by a drop in synaptic glutamate levels during prolonged photoreceptor illumination. The second mechanism, discussed in chapter 3, is mediated by cGMP, and is dependent upon activation of cGMP-dependent kinase. An increase in intracellular cGMP concentration reduces the ability of glutamate to close the mGluR6 gated transduction channel, as evidenced by a shift in the dose response relation when cGMP is included in the recording pipette. This increases the On bipolar cell sensitivity to small fluctuations in synaptic glutamate, thereby allowing for detection of low intensity stimulation, such as dim light. In chapter 4, I show that this increased sensitivity of the On bipolar cell is transmitted to the postsynaptic AII amacrine cell, thereby affecting signaling throughout the retinal On pathway. The result is increased visual sensitivity during conditions of low ambient light, i.e. night vision.;As a whole, the work presented here describes how the properties of a single synapse can be modified to respond optimally over a wide range of stimulation.