Our work focuses on specialized circuitry in the inner retina. Having examined several inner retinal synapses in physiological detail, we now seek to understand how these synapses contribute to visual processing in the surrounding circuitry. We combine electrophysiology, imaging approaches and cellular/network modeling to explore dendritic integration in directionally-selective ganglion cells (DSGCs). Specifically, we have examined how directionally tuned synaptic inhibition, coming from starburst amacrine cells, and NMDA receptor-mediated input from bipolar cells combine in DSGC dendrites to achieve perfectly multiplicative scaling of postsynaptic potentials, enabling directional signals to become larger with no change in directional selectivity. We are in the process of extending these findings into a more generally applicable study of how NMDA receptor inputs normalize the interaction between excitation and inhibition. We are studying this in ganglion cells, but the underlying concepts are likely to apply to many different neuronal cell types in the brain. Our work on feedback inhibition has led us to undertake a long-term effort to understand, in a systematic way, how amacrine cells contribute to visual signaling in the inner retina. With over 40 different amacrine cell subtypes, this prospect can be a bit overwhelming. To start, we have examined visual processing in starburst amacrine cells (SACs). In a collaboration with Kevin Briggman (NINDS) and Robert Smith (Penn), we found that SACs in mouse retina receive their synaptic inputs in a different pattern compared with rabbit retina (the classical model for direction selectivity). We have continued this work to examine directional responses in individual SAC synapses. We find that direction selectivity is quite variable among neighboring SAC synapses, although groups of synapss exhibit highly correlated responses, suggesting that they operate within common functional compartments (computational units). This functional compartmentalization is enhanced by lateral inhibition within the SAC network. In addition, these experiments have provided insights into the source and impact of noise within the direction selective circuitry. A manuscript is nearing submission. We are also examining visual signaling in other amacrine cell types, using the same approaches that have worked well for us in the SACs. This involves visualizing genetically labeled amacrine cells, filling individual cells with a fluorescent calcium indicator, and then measuring dendritic Ca responses evoked by visual stimuli. We hope to understand the signaling mechanisms that underlie specific visual computations that occur in amacrine cell dendrites.
