Stewart Bloomfield, PhD
33 West 42nd Street New York, NY 10036
Functional Roles of Gap Junctions in Retinal Physiology and Pathology
Historically, the work in our laboratory has been directed at understanding the cellular mechanisms of information processing and cell-to-cell communication in the mammalian retina. The retina is an exquisite model system to study signal processing in the CNS, owing to its relative simplicity of organization, accessibility, and the ability to be maintained in an in vitro environment while still remaining responsive to natural light stimulation. Although there are only five major types of neurons in the retina, they include some 80 morphological subtypes classified by differences in soma/dendritic/axonal architecture. Inherent to this classification scheme is the notion of structure/function correlations, suggesting that an equally large pool of physiological and functional subtypes exist as well. Work in my lab over the past 30 years has elucidated the response physiology of numerous neurons in the mammalian retina, including subtypes of horizontal, bipolar, amacrine and ganglion cells. We use a wide range of techniques in the lab, including patch clamp and multi-electrode array recordings, confocal and multi-photon microscopy, channelrhodopsin expression, histological and morphological staining paradigms as applied to transgenic and knockout models.
Most recently, my lab has focused on the role of gap junctions and electrical synaptic transmission in the retina. The wide distribution and diverse connexin subunit makeup of gap junctions in the retina is unique in the CNS and, as a result, it has become arguably the best model system for the study of electrical neurotransmission in the brain. We have shown the electrical transmission via gap junctions plays a multitude of roles in image processing, including contrast sensitivity, neural adaptation, synchronization of ganglion cell activity, and direction selectivity critical to the optokinetic response. Further, we have shown that gap junction coupling between neurons is highly plastic and light dependent. For example, we recently reported that during daylight the electrical coupling between ganglion cells is increased, thereby altering their activity so that additional visual information can be passed across the limited bandwidth of the optic nerve.
In the past few years, we have translated our basic research in a more clinical direction. Neuronal loss through cell death is a hallmark of many pathological conditions in the nervous system, including Alzheimer’s and Huntington’s disease in the brain and diabetic neuropathy, ischemic retinopathy, retinitis pigmentosa (RP) and glaucoma in the retina. The major pathways underlying cell death have been well characterized and they include a number of molecularly-regulated cascades. In addition, converging evidence indicates that intercellular communication through gap junctions underlies secondary or bystander neuronal death in a variety of neurodegenerative diseases. In this scheme, gap junctions form conduits by which toxic metabolites are transferred from a dying cell to its neighbors leading to their death. Interestingly, our data indicate that gap junction-mediated secondary cell death is responsible for ~75% of the total loss of ganglion and amacrine cells in the retina under ischemic and excitotoxic conditions. Our results also suggest that the cohort of gap junctions, based on the connexins they express, play differential roles in secondary cell death dependent on the type of initial insult.
Taken together, these data support the novel hypothesis that gap junction-mediated secondary cell death is responsible for most of the cell loss in the retina associated with a variety of primary insults. Further, our results suggest that the type of gap junctions expressed by different neuronal subtypes is a contributing factor to selective neuronal vulnerability found under different pathological conditions, including glaucoma. The long-term goal of this new phase of our research is to elucidate novel therapeutic strategies for targeting specific gap junctions to limit the cell loss associated with a number of retinal neurodegenerative diseases.
- State University of New York at Stony Brook, BS, 1976, Mathematics/Biology
- Washington University, St. Louis, Ph.D., 1981, Neural Science
- Harvard University, Postdoc, 1981-1983, Retinal Pharmacology
- 1983-1988: Research Assistant Professor, Department of Neurobiology; State University of New York at Stony Brook
- 1988-1995; Assistant Professor, Departments of Physiology Neuroscience and Ophthalmology, New York University School of Medicine
- 1995-2002; Associate Professor, Departments of Physiology & Neuroscience and Ophthalmology, New York University School of Medicine
- 1997-2012; Director of the Graduate Program in Neuroscience & Physiology, New York University School of Medicine
- 2002-2012; Professor of Physiology & Neuroscience and Physiology; New York University School of Medicine
- 2003-2008; Director of Research, Department of Ophthalmology, New York University School of Medicine
- 2013-Present; Professor, State University of New York College of Optometry
- 2013-Present; Director of the Graduate Center for Vision Research, State University of New York College of Optometry
- 2013-Present; Associate Dean for Graduate Studies and Research, State University of New York College of Optometry
- 1978-1981; NIH Predoctoral Fellowship, Graduate Program in Neural Science, Washington University School of Medicine, St. Louis
- 1981-1983; NIH Postdoctoral Fellowship, The Biological Labs, Harvard University
- 1989-1991; Research to Prevent Blindness Research Manpower Award
- 1993-1995; Research to Prevent Blindness Benedict and Miriam Wolf Special Scholar Award
- 1999; Dean’s Recognition Citation for Excellence in Medical Education, New York University School of Medicine
- 2006; Brian B. Boycott Award for Achievement in Vision Research, Federation of American Societies for Experimental Biology
- 1985-Present; Ad hoc Reviewer, NSF Sensory Physiology Section
- 1998-2002; Permanent Member, NIH VISC Study Section
- 1998-Present; Ad hoc reviewer for Intramural Grants, Veterans Administration
- 2000-2002; Editorial Board, Visual Neuroscience
- 2002-2008; Associate Editor; Visual Neuroscience
- 2002; Member, NIH ZEY1 VSN 08 Study Section, NEI Institutional and Professional School Training Grant Applications
- 2003; Chairman, NIH ZRG1 CDF-1 Special Emphasis Panel, Retinal Cell Development and Function
- 2003-2005; Program Committee Member, ARVO, Visual Neurophysiology Section
- 2006; Program Committee Chairman, SRVO, Visual Neurophysiology Section
- 2006-2010; Scientific Advisory Committee, Fight for Sight Foundation
- 2008; Member, NEI ZEY1 VSN 07 Training (Grant) and Scientific Meeting Reviews
- 2010; Ad hoc Reviewer, NIH BDPE Study Section
- 2011; Ad hoc Reviewer, NIH BDPE Study Section
NIH R01 EY007360
Functional Roles of Gap Junctions in Visual Processing in the Retina
This experimental program examines the diverse roles of gap junctions and electrical synaptic transmission in the retina related to contrast detection, efficacy of signaling, and object recognition. Additional studies are proposed to elucidate the electrical circuits subserved by the over 20 subtypes of ganglion cells in the mouse retina.
Deans, M., B. Völgyi, D. Goodenough, S.A. Bloomfield and D. Paul (2002). Role of gap junctions in the transmission of rod signals in the retina: an electrophysiological study of a connexin36 knockout mouse. Neuron 36:703-712.
Hu, E. and S.A. Bloomfield (2003). Gap junctional coupling underlies the short-latency spike synchrony of retinal alpha ganglion cells. Journal of Neuroscience. 23:6768-6777.
Chow, R.L., B. Völgyi, R.K. Szilard, D. Ng, C. McKerlie, S.A. Bloomfield, D.G. Birch and R.R. McInnes (2004). Control of late off-center cone bipolar cell differentiation and visual signaling by the homeobox gene, Vsx1. Proceedings of the National Academy of Sciences USA 101:1754-1759.
Ozaita, A; J., Petite-Jacque, B. Völgyi, C.S. Ho, R.H. Joho, S.A. Bloomfield and B. Rudy (2004). A unique role of Kv3 voltage-gated potassium channels in starburst amacrine cell signaling in mouse retina. Journal of Neuroscience 24:9335-9343.
Bloomfield, S.A. and B. Völgyi (2004). Function and plasticity of homolgous coupling between AII amacrine cells in the mammalian retina. Vision Research 44:3297-3306.
Völgyi, B, M. Deans, D. Paul and S.A. Bloomfield (2004) Convergence and segregation of the rod pathways in mammalian retina. Journal of Neuroscience 24:11182-11192.
Petit-Jacque, J. and Bloomfield, S.A. (2005). Spontaneous oscillatory activity of starburst amacrine cells in the mouse retina. Journal of Neurophysiology. 94:1770-1780.
Völgyi, B., J. Abrams, D.L. Paul and S.A. Bloomfield (2005). Morphology and tracer coupling patterns of alpha ganglion cells in the mouse retina. Journal of Comparative Neurology. 492:66-77.
Ackert, J.A., S.H. Wu, J. Lee, J. Abrams, E. Hu, I. Perlman and S.A. Bloomfield (2006). Light-induced changes in spike synchronization between coupled ON direction selective ganglion cells in the mammalian retina. Journal of Neuroscience. 26:4206-4215.
Petit-Jacques, J. and S.A. Bloomfield (2008). Synaptic regulations of the light-dependnet oscillatory currents in starburst amacrine cells of the mouse retina. Journal of Neurophysiology 100:993-1006.
Ackert, J.A., Völgyi, B., R. Farajian and S.A. Bloomfield (2009). GABA blockade unmasks an OFF response in ON direction selective ganglion cells in the mammalian retina. Journal of Physiology 587:4481-4495.
Bloomfield, S.A. and B. Völgyi (2009). The diverse functional roles and regulation of neuronal gap junctions in the retina. Nature Reviews Neuroscience 10:495-506.
Völgyi, B, Chheda, S. and S.A. Bloomfield (2009). Tracer coupling pattern of the ganglion cells subtypes in the mouse retina. Journal of Comparative Neurology 512:664-687.
Pan, F.,Paul, D.L., Bloomfield, S.A.and Völgyi, B. (2010). Connexin36 is required for gap junctional coupling of most ganglion cell subtypes in the mouse retina. Journal of Comparative Neurology 518:911-927.
Hu, E., Pan, F, Völgyi, B. and Bloomfield S.A. (2010). Light increases the gap junctional coupling of retinal ganglion cells. Journal of Physiology 588:4145-4163.
Osterhout, A., Josten, N., Yamada, J., Pan, F., Wu, S.W., Nguyen, P.L., Panagiotakos, G., Inoue, Y.U., Egusa, S.F., Volgyi, B., Inoue, T., Bloomfield, S.A., Barres, B.A., Berson, D.M., Feldheim, D.A. and Huberman, A.D. (2011). Cadherin-6 mediates axon-target matching in a non-image-forming visual circuit. Neuron 71:632-639.
Farajian, R., Pan, F., Akopian, A., Völgyi, B. and Bloomfield, S.A. (2011). Masked crossover excitation between the ON and OFF visual pathways in the mammalian retina. Journal of Physiology 589:4473-4489.
Bloomfield, SA and Völgyi B (2012) Mind the gap: the functional roles of neuronal gap junctions in the retina. In: The New Visual Neurosciences. J.S. Werner and L.M. Chalupa, eds. MIT Press. In press.