Biophysics of visual adaptation: tuning retinal microcircuits for vision in starlight, twilight, and daylight

During a day and night cycle, our eyes are exposed to intensities of light that vary by a factor of approximately 10^10. Our vision is fully operative throughout this huge range, despite the fact that the spike rate of retinal ganglion cells varies by only a factor of 10^2. The ability of the ganglion cells to cover this range is made possible through mechanisms at both receptoral and post-receptoral levels. This phenomenon represents a classical, ?text book? example of sensory adaptation. Whereas receptoral adaptation is understood in molecular detail, the mechanisms of post-receptoral circuit adaptation are much less known, but are thought to include modulation of gap junction (electrical) coupling that somehow optimizes the circuits for changing background light intensity. The project has aimed to determine the cellular and molecular mechanisms that mediate the tuning of an electrically coupled network of retinal interneurons (the so-called ?AII? amacrine cells) that play an important role in visual processing in starlight, twilight and daylight. Specifically, the project has investigated the involvement of the neurotransmitters glutamate and dopamine, the intracellular 2nd messenger cAMP, and the enzymes PKA and Ca2+/CaMKII in regulating the strength of coupling between AII amacrine cells. In addition, the project has investigated the intracellular Ca2+ dynamics of AII amacrine cells evoked by specific stimuli, potentially linking the Ca2+ dynamics to a role in regulating the strength of coupling. We have found that glutamate, via activation of NMDA receptors, evokes influx of Ca2+ that triggers a reversible reduction of the strenght of electrical coupling between AII amacrine cells. In addition, the project has investigated how synaptic integration in AII amacrines is influenced by the strength of electrical coupling. We have performed experiments where we have filled AII cells with fluorescent dyes, reconstructed their morphology after imaging with 2-photon microscopy and performed a detailed morphometric analysis of the branching pattern of these cells. Because such morphological reconstructions can be extremely time-consuming, we also developed software for semi-automatic reconstruction that requires minimal user-input and is much less time-consuming than classical, manual reconstruction. Finally, morphological reconstructions together with electrophysiological recordings were combined to develop computer models that were used to simulate the signal processing and synaptic integration in the AII amacrine cells. The project has used a combination of electrophysiological (dual recording of electrically coupled cells), pharmacological (perturbation of intracellular transduction via patch pipette perfusion), imaging (multi-photon excitation and confocal microscopy), and computational modeling methods and has increased our understanding of how the plasticity of electrical synapses can optimize signal processing in the CNS.

During a 24 hour cycle, our eyes are exposed to intensities of light that vary by a factor of 10 log units. Our vision is fully operative throughout this range, despite the fact that the spike rate of retinal ganglion cells varies by only a factor of 2 lo g units. The visual system accomplishes this through retinal mechanisms that involve both photoreceptors and neural circuits. Whereas transduction and adaptation in photoreceptors are understood in molecular detail, very little is known about mechanisms o f adaptation postsynaptic to the photoreceptors. These mechanisms are thought to involve modulation of gap junction (electrical) coupling that channels the flow of visual signals into specific circuits and somehow optimizes these circuits for changing bac kground light intensity. The project aims to determine the cellular and molecular mechanisms that mediate the tuning of an electrically coupled network of retinal interneurons (AII amacrine cells) that plays an important role in visual processing across a wide range of light intensity, including starlight, twilight and daylight. Specifically, the involvement of dopamine, cAMP/PKA and CaMKII in regulating the strength of electrical coupling will be investigated. In addition, we will examine the intracellul ar Ca2+ dynamics of AII amacrines, potentially linking changes in Ca2+ to the regulation of coupling. Finally, the project aims to determine how synaptic integration and signal processing in AII amacrines are influenced by the strength of electrical coupl ing interacting with intrinsic ionic conductances. The project will use a combination of electrophysiological (single- and multi-electrode recording), pharmacological (perturbation of intracellular transduction via patch pipette perfusion), imaging (multi -photon excitation microscopy), and computational modeling methods and has the potential to advance our understanding of how plasticity of electrical synapses can optimize signal processing in the CNS.