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). We find, consistent with previous work in the literature, that DS computation does not require NMDA receptors in DSGCs. They do, however, enhance the fidelity of DS signals by multiplicatively amplifying postsynaptic responses. This enables the DSGC to fire more avidly specifically in response to motion in the preferred direction. Network simulations suggest that this multiplicative amplification requires directionally tuned inhibition that has been shown to come from starburst amacrine cells. This work shows how NMDA receptors accomplish a specific computation in response to physiological stimuli that enhances the fidelity of signal transmission to downstream targets. A manuscript is fully developed and nearing submission. In addition, we are exploring mechanisms by which excitation and inhibition remain balanced in the DS circuitry over a range of stimulus conditions. A manuscript is in preparation. 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 kinds of amacrine cell, this a daunting prospect. To start, we have identified narrow- and wide-field amacrine cells that can be identified and manipulated by genetic means. We have acquired mouse lines in which CRE is expressed specifically in certain amacrine cells and then cross them with floxed lines enabling the CRE-expressing neurons to be silenced chemically (through CRE-dependent expression of designer receptors exclusively activated by designer drugs). We have successfully imaged dendritic signaling in these cells using genetically encoded calcium indicators. In the near future, we will examine the impact of silencing these cells (with genetically encoded receptors that respond only to an exogenous, otherwise inert ligand) on ganglion cell signaling using a microelectrode array. These approaches enable us to examine signaling mechanisms that are not accessible with somatic electrophysiological recordings to understand functional themes within this complex, diverse cell class. We are also studying how the biophysical properties of synapses and neurons change with different phases of the circadian cycle or dark adaptation. Initially we have focused on changes in BK channel function in AII amacrine cells, which play distinct roles in night and daytime vision. A manuscript containing initial physiological work is nearing submission, and we have begun to collaborate with Dr. Robert Smith to develop circuit models to evaluate the impact of changes in the retinal circuitry.
