The research interests of our laboratory concern molecular mechanisms underlying synaptic transmission and neural function in the brain. We use the vertebrate retina as a model system because of its accessibility, its known function, and its accurately controllable natural input. We have two research objectives:
(1) To understand how synaptic events in the retina encode and process various attributes of visual images (such as brightness, ON/OFF signals, contrast, shape, motion and color), and thereby elucidate general operational principles employed by synaptic networks in the brain for processing natural neuronal signals. By using microelectrode, patch clamp, multi-electrode array and optical recording techniques in conjunction with immunocytochemistry, fluorescent dye injection, and confocal and electron microscopy, we study synaptic circuitry mediating visual information processing in amphibian and mammalian retinas. We investigate how feedback, feedforward and lateral synaptic circuits regulate visual signals in the retina, and how these circuits are used as general functional units for neural computations in the brain. We also examine how retinal signals are modulated by visual adaptation, and derive general principles for use-dependent synaptic plasticity under natural operational conditions. Additionally, we formulate computational models for signal processing by parallel channels in the retina, which can be useful for analyzing signaling pathways in the visual system and the entire brain.
(2) To elucidate how cellular, synaptic, and genetic factors mediate retinal dysfunction in diseased mouse models. The mouse models we study can be divided into two broad categories. The first is pathway-specific knockout/mutant mice, in which specific molecules or types of cells in the synaptic circuitry are deleted, and thus parallel signaling pathways can be analyzed separately. These include mice that lack rod response (rod transducin knockout, Trα -/-), lack cone response (cone transducin mutation, GNAT2 cpfl3), lack connexin36 gap junction protein (Cx36 -/-) and lack rod bipolar cells (Bhlhb4 -/-). The second type of mouse models is associated with retinal degeneration in eye and neurological disorders. We characterized mechanisms of retinal degeneration in the Spinocerebellar Ataxia type 7 (SCA7) mutant knockin and the Bardet-Biedl Syndrome 4 (BBS4) knockout mouse model, as well as mechanisms of ganglion cell sensitivity loss in two glaucoma mouse models. We have also studied photoreceptor and bipolar cell dysfunction after deletion of phototransduction proteins or transcription factors in GCAP1/2 -/-, Beta2 (NeuroD)-/- and Bhlhb4 -/- mice. Recently, our lab has begun to investigate the use of viral gene therapy in rescuing certain mouse models of retinal disease.