Professor - Department of Ophthalmology, the Camille and Raymond Hankamer Chair in Ophthalmology Professor - Department of Neuroscience Professor - Department of Molecular Physiology and Biophysics Ph.D., Harvard University, 1979 Cullen Eye Institute Baylor College of Medicine, NC-205 Houston, Texas 77030 Telephone: 713-798-5966 - Fax: 713-798-6457 Email: swu@bcm.tmc.edu Website: neuro.bcm.edu/wu

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.  Our overall goal is 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 to elucidate how cellular, synaptic, and genetic factors mediate retinal dysfunction in diseased states.

There are three research projects in our laboratory:

(1) By using microelectrode, patch clamp, 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 focus our studies on how ion channels, neurotransmitter receptors and transporters, and second messengers in individual retinal synapses mediate rod/cone inputs, ON/OFF signals, and the center-surround receptive field organization of bipolar cells and ganglion cells.  We also examine how synaptic plasticity occurs in the retina and how retinal signals are modulated by visual adaptation.  Additionally, we correlate various attributes of bipolar cell, amacrine cell, and ganglion cell light responses with their morphology and synaptic connectivity, especially the patterns of axonal and dendritic stratification in the inner plexiform layer.  This allows us to derive computational algorithms for signal segregation and integration in the visual system.

(2) We study gene regulation of retinal function and eye disorders in genetically manipulated mouse models by using electroretinogram (ERG), patch clamp recording, multi-electrode array, immunocytochemistry, and molecular biological techniques. The mouse models we studied include that with a deletion of the transcription factor gene BETA2/NeuroD, deletion of connexin36, deletion of rod transducin, the GCAP knockout and knock-in mice and a BBS (Bardet-Biedl Syndrome) knockout mouse model. We examined how various transcription factors and proteins affect the structure and function of individual retinal cells, and how they may mediate degenerative diseases in the retina.

(3) We also study the mechanisms of retinal ganglion cell degeneration in glaucoma mouse models. Glaucoma is a leading cause of irreversible blindness in the US and throughout the world, and it is associated with elevated intraocular pressure (IOP) and an end result of retinal ganglion cell death.  We are interested in understanding how various pathological conditions affect retinal ganglion cell function and also what pharmacological and genetic tools can be used to prevent or slow down the degenerative process of retinal ganglion cells in glaucoma.  We use a chronic (the DBA/2J mutant mouse) and an acute (laser-induced high-IOP mouse) model to study how glaucoma and elevated IOP initiate degenerative processes in the inner retina and how dysfunction in individual synapses are responsible for visual sensitivity loss and ganglion cell death in glaucoma.

In summary, we employ electrophysiological, pharmacological, anatomical, and molecular genetic techniques in unison to study how electrical and chemical synapses in the retina process light-evoked signals in the visual system.  We also investigate how various physiological, biochemical, and genetic factors regulate retinal function and dysfunction. Results obtained will be integrated into a comprehensive and coherent description of how individual molecular and synaptic events in the retina mediate visual information processing and eye disorders.  Such description will not only set a firm foundation for our understanding of the visual system, but also, because of the retina’s unique advantage of known natural input, render a fine example of how neural circuits in the brain process natural signals from our daily environment.

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Pang, J.J., Gao, F., Lem, J., Bramblett, D.E., Paul, D.L. and Wu, S.M. (2010) Direct rod input to cone BCs and direct cone input to rod BCs challenge the traditional view of mammalian BC circuitry. Proc. Nat. Acad. Scien. (USA), 107, 1, 395-400.

Barrow, A. and Wu, S.M. (2009) Low conductance HCN1 channels augment the frequency response of rod and cone photoreceptors. J. Neuroscience.  29, 5841-5853.

Zhang, A.J. and Wu, S.M. (2009) Receptive fields of retinal bipolar cells are mediated by heterogeneous synaptic circuitry. J. Neuroscience,  29 (3), 789-797.

Zhang, J. and Wu, S.M. (2005) Physiological properties of rod photoreceptor coupling in the tiger salamander retina. J. Physiology, 564.3, 849-862.

Bramblett, D.E., Pennesi, M.E., Wu, S.M. and Tsai, M.J. (2004) Bhlhb4 in rod bipolar cell maturation. Neuron, 43,6,779-793.

Pang, J. J., Gao, F. and Wu, S. M. (2004) Light-evoked current responses in rod bipolar cells, cone depolarizing bipolar cells, and AII amacrine cells in dark-adapted mouse retina. J. Physiology. 558.3, 897-912.

Pang, J.J., Gao, F. and Wu, S. M. (2004) Stratum-by-stratum projection of light response attributes by retinal bipolar cells. J. Physiology, 558.1, 249-262.

Zhang, J. and Wu, S.M. (2004) Connexin35/36 gap junction proteins are expressed in photoreceptors of the tiger salamander retina. J. Comp. Neurol. 470, 1-12.

Pang, J. J., Gao, F. and Wu, S. M. (2003) Light-evoked excitatory and inhibitory synaptic inputs to ON and OFF a ganglion cells in the mouse retina. J. Neuroscience 23, 14, 6063-6073.

Pennesi, M.E., Howes, K.A., Baehr, W., and Wu, S.M. (2003) GCAP1 rescues cone photoreceptor responses in GCAP1/GCAP2 knockout mice. Proc. Nat. Acad. Scien. (USA) 100, 11, 6783-6788.

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Sam and Bertha Brochstein Award for Outstanding Achievement in Retina Research, Retina Research Foundation, 1987.

Dolly Green Scholars Award, Research to Prevent Blindness, Inc. 1989.

Marjorie W. Margolin Prize, Retina Research Foundation, 1991.

Senior Scientific Investigators Award, Research to Prevent Blindness, Inc. 1997.

James M. Barr Award for Outstanding Retina Research in the Greater Houston Area, Retina Research Foundation, 1998.

James M. Barr Award for Outstanding Retina Research Achievement, Retina Research Foundation, 2005.

The Boycott Prize, FESEB 2006 “Retinal Neurobiology and Visual Processing”

Ludwig von Sallmann Prize, International Society for Eye Research, 2008.

Friedenwald Award, Association for Research in Vision and Ophthalmology, 2009.

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• Cameron Cowan (Neuroscience)
• David Simons (Neuroscience)

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Schematic diagram of synaptic connections of photoreceptors, bipolar cells, amacrine cells and alpha ganglion cells in the mammalian retina. R: rod, MC: M-cone, SC: S-cone, HBCMC/R: Mixed M-cone/rod hyperpolarizing bipolar cell; HBCMC: M-cone dominated hyperpolarizing bipolar cell; HBCSC: S-cone dominated hyperpolarizing bipolar cell; DBCC2: type 2 cone depolarizing bipolar cell, DBCC1: type 1 cone depolarizing bipolar cell; DBCR2: type 2 rod depolarizing bipolar cell; DBCR1: type 1 rod depolarizing bipolar cell. Note that BCs with the most rod inputs have axon terminal endings near the two margins of the IPL whereas those with most cone inputs bear axons ramifying in the central regions of the IPL, similar to the rules set forward by the salamander BCs (part A).  ACM1: M-cone dominated depolarizing amacrine cell; ACM2: M-cone dominated ON-OFF amacrine cell; AII: AII amacrine cell; A17/S1: A17 amacrine cell; sOFFαGC: sustained OFF alpha ganglion cell; tOFFαGC: transient OFF alpha ganglion cell; ONαGC: ON alpha ganglion cell; green: rods and rod BCs; blue: M-cones and M-cone BCs, purple: S-cone and S-cone BCs; light orange: GABAergic ACs; dark orange: glycinergic ACs; grey: αGCs; arrows: chemical synapses (red: glutamatergic, black: GABAergic, blue: glycinergic, “+” sign-preserving, and “-“ sign-inverting),  zigzag (red): electrical synapses, PRL: photoreceptor layer, OPL: outer plexiform layer, INL: inner nuclear layer, IPL: inner plexiform layer (a: sublamina a, b: sublamina b), GCL: ganglion cell layer.

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