Dr. Famiglietti, M.D., Ph.D (Boston University, 1972) pursued postdoctoral studies at the National Eye Institute (NIH), Keio University (Tokyo), and Washington University (St. Louis), as an Alfred P. Sloan Foundation Fellow in Neuroscience. Assistant professor at Wayne State University in 1979, and then associate professor at the University of Calgary, as an Alberta heritage Foundation (AHFMR) Scholar, he was funded by N.I.H, by the AHFMR, and by the Canadian MRC and NSERC. In 1995, Dr. Famiglietti came to Brown as a clinical trainee in neuropathology, and has held adjunct appointments in the Departments of Neuroscience, Surgery (Ophthalmology), and Molecular Pharmacology, Physiology and Biotechnology. Dr. Famiglietti's research interests concern retinal information processing and neural architecture of retinal ganglion cells. Recent studies of degeneration and regeneration of ganglion cells have led to development of in vitro preparations for the study of regeneration. Dr. Famiglietti has published in Science, and continues to publish peer-reviewed papers in scientific journals.
Edward V. Famiglietti, M.D., Ph.D.
Summary of Research Accomplishments and Research Interests
A. Scientific Achievements
* Thirty-five years of research on the retina.
* Discoverer of the bisublaminar organization of ON and OFF pathways in the inner retina.
* Co-discoverer of the organization of rod and cone pathways in mammalian retina.
* Discoverer of starburst (cholinergic) amacrine cells in the retina.
* First or sole author of thirty-two refereed papers on the retina and visual system in Science, Vision Research, Visual Neuroscience, Journal of Neuroscience, Journal of Comparative Neurology and Brain Research, and an author on refereed papers in Investigative Ophthalmology, and other journals.
* Author of more than forty abstracts on retina and visual system.
* Invited guest-speaker at university departments on more than sixty occasions at universities including Oxford, Cambridge, Harvard, and M.I.T.
* Invited speaker at seventeen international symposia.
* Organizer of an international symposium on 'retinal ganglion cells: form and function' at the annual meeting of the Society for Neuroscience.
* Co-Organizer of a satellite symposium of the International Physiological Congress on 'retinal development and regeneration'.
B. Research Activity and Research Goals
Basic Retinal Neurobiology-Fundamental Aspects of Visual Information Processing in the Retina
The first of Dr. Famiglietti's studies in retina were directed identifying the cellular components of the retina and understanding organization or 'neural architecture' of their neural circuits, which underlie the processing of visual information in the retina. This work, elucidating the ON and OFF pathways of the retina, as well as the specific differences between rod (night vision) and cone (day vision) pathways of mammalian retina, also included the identification by structural criteria of functional types of retinal ganglion cell that transmit information, decoded and processed in the retina, to various higher centers of the visual brain. In addition, this work focussed on the roles of key retinal processing units, the amacrine cells, identified by neurotransmitters that they use, in particular, amacrine cells containing GABA, the brain's most common inhibitory neurotransmitter, and amacrine cells containing acetylcholine, one of the brain's most important excitatory neurotransmitters. These two neurotransmitters play important roles in retinal motion sensitivity and directional selectivity. Elucidating the neural circuitry underlying these mechanisms was the major focus of the latter half of this period of work.
A research effort of longstanding, presently nearing completion, is the morphological classification of retinal ganglion cells in rabbit. In all, between 42 and 45 (morphological) types of ganglion cell have been identified in rabbit. The well-studied physiology and pharmacology of rabbit ganglion cells shows the greatest diversity of types among mammals identifiable by visual stimuli. Hence rabbit ganglion cells are most readily characterized in terms of visual function. In a comparison of morphological and physiological types, this system offers the greatest promise of understanding the functional diversity of parallel visual pathways in mammalian and ultimately the operation of these pathways in human retina.
A structural-functional correlation has been made for seven types of large, rapidly conducting ganglion cells. We are attempting to understand how these ganglion cells are distributed across the retina, as well as what the requirements are in mammalian vision for such diversity.
Subject to finding priorities, a parallel undertaking of ganglion cell identification and functional classification will be initiated in mouse retina, and the rabbit library of types will be used to guide the analysis in mouse. Mouse retina will afford the opportunity to extend such studies to the level of gene expression. Fundamental questions can then be addressed concerning the generation of ganglion cell diversity in mammalian retina, and the answers will permit the discrimination of morphological-functional types by their molecular genetic signatures.
Retinal Development and Genetics
For some years, pilot developmental studies have been underway in Dr. Famiglietti's laboratory, exploring the pattern of differentiation of retinal ganglion cells and amacrine cells. More recent developmental studies examining the early expression of the amacrine cell neurotransmitters GABA and acetylcholine showed that these cells and their transmitters are present and play an important, but as yet undefined, role in retinal development just after birth, before the neural circuits that make sight possible are connected. The importance of understanding these developmental mechanisms is the potential they have for reinnervating a retina that has been damaged by diseases that destroy the retina, such as macular degeneration and diabetic retinopathy. Presumably, restoration of the retina by the integration of stems cells or embryonic retinal grafts into retinal layers and circuits, will involve the recapitulation of developmental sequences, built into the genetic programs of the immature, undifferentiated neural cells.
Retinal Ganglion Cell Degeneration, Rescue and Regeneration
Beginning in l990, a pilot project was initiated in Dr. Famiglietti's laboratory to develop an animal model in rabbit of retinal ganglion cell regeneration by nerve grafting after damage to the optic nerve. Prior work in rat visual system suggested that this paradigm would be feasible, despite the greater difficulties of working with rabbits. As noted above, a great deal more is known about the ganglion cells of rabbit retina than about those of any other animal. In the adult rabbit retina in vivo, it was found that the large ganglion cells (see above) mounted the earliest and most vigorous response to axonal injury. They were among the earliest to die and among survivors the most likely to form new axons. The survival characteristics of different types of ganglion cell, after pressure or anoxic insult, could reveal what types of visual functions might be rescued by therapeutic intervention in cases of optic nerve and retinal ganglion cell damage that occurs, for example, in glaucoma, as well as in Alzheimer's Disease.
One of the principal goals of the development of an in vitro mouse retinal preparation (see below) has been to allow the study of conditions and agents favoring neuronal rescue or leading to neuronal death under controlled conditions and in the presence of known concentrations of agents.
A second principal goal of the retinal organ culture preparation is to study the integration of stem cells supplied to replace lost ganglion cells.
Growth Factors in Retinal Development and Regeneration
Dr. Famiglietti's work initiated in Dr. Elaine Bearer's laboratory at Brown University, during a period of clinical pathology training, and more extensive studies, subsequently, carried out in Dr. Jeremy Nathans' laboratory at Johns Hopkins University, at in Dr. Colin Barnstable's laboratory at Yale University, have been directed toward methods of tissue culture, and the development of an embryonic (perinatal) mouse retinal organ culture system.
Preliminary results of the mouse retinal organ cell culture experiments show that a combination of brain growth factors, including 'brain derived neurotrophic factor' (BDNF) can aid in the rescue retinal ganglion cells. Other factors, including specific media supplements were important for ganglion cell survival. The axons of the cells were cut off in removing the retina from the eye, and thus the ganglion cells would otherwise undergo apoptosis and die within three days. In the mouse organ culture model, under specific culture conditions, ganglion cells survived for the length of the study: more than two weeks. A subsequent pilot study showed that immature mouse ganglion cells could be isolated by immunopanning and plated upon in vitro mouse retina with the formation of neurite outgrowth suggestive of dendrites. The focus of new work will be to test whether plated ganglion cells can establish functional connections with presynaptic neurons.
Because mouse genetics is so far advanced over that in other mammals, and in view of the availability of many gene "knockout" and overexpression mutants in mice, answers to questions about developmental programs that may be of use in regeneration and restoration of human retinal function will very likely be discovered in mouse models.
Growth Factors and the Control of Retinal Angiogenesis
Recently, a great deal of excitement has been generated in the world of medical research, particularly in the area of tumor growth, around the subject of angiogenesis and the control of blood vessel proliferation. In mouse models, antagonists of tumor angiogenesis shrink the tumors. In retina, abnormal angiogenesis is the critical final common pathway that leads to retinal damage in many eye diseases, including diabetic retinopathy, macular degeneration, and vascular changes due to aging. The cytokine, vascular endothelial growth factor (VEGF) or vascular permeability factor, has been confirmed as the causative factor in retinal blood vessel proliferation, both normally during development, and abnormally in the vascular proliferation characteristic of major eye diseases. As Dr. Famiglietti and colleagues in neuropathology and ocular pathology have shown, however, VEGF is present normally in most neurons and glial cells of adult human retina. Thus, retinal neurons, highly sensitive to ischemia and anoxia, appear well equipped to regulate their own blood supply. Unfortunately, ischemic insults to retina apparently provoke an overexpression of VEGF and consequent vascular proliferation and growth of abnormal vessels that may eventually disrupt and destroy the retina by several mechanisms.
Inhibitors of the action of VEGF on vascular endothelial cells have already proven of value in reducing abnormal angiogenesis in animal models. In cases of human eye disease, after abnormal vessels have already formed, it may be possible to apply agents like those used to eliminate the vessels in tumors to halt the deterioration of the retina. This strategy, coupled to that developed for neural transplantation and regeneration, may ultimately be successful in restoring the integrity of the retina and adjacent structures, as well as in recovery from stroke and vascular diseases of aging. If this therapeutic strategy is to be successful, it may be necessary for agents to discriminate reliably between abnormal and normal retinal vessels. In the likely case that both abnormal and normal vessels will be affected, it will be necessary to invoke neuroprotective mechanisms to safeguard vulnerable brain and retinal neurons.
Famiglietti E.V. (2009) Bistratified ganglion cells of rabbit retina: Neural architecture for contrast-independent visual responses, Visual Neurosci., 26 (2), 195-213.
Famiglietti E.V. (2008) Wide-field cone bipolar cells and the blue-ON pathway to color-coded ganglion cells in rabbit retina, Visual Neurosci., 25, 53-66.
Famiglietti E.V. (2005) Synaptic organization of "complex" ganglion cells in rabbit retina: type and arrangement of inputs to directional selective and local edge detector cells, J. Comp. Neur. 484, 357-391.
Famiglietti E.V. (2005) "Small-tufted" ganglion cells and two visual systems for the detection of object motion in rabbit retina, Visual Neurosci. 22, 509-534.
Famiglietti E.V. (2004) Class I and class II ganglion cells of rabbit retina: a structural basis for X and Y (brisk) cells, J. Comp. Neur. 478, 323-346.
Famiglietti E.V. (2002) A structural basis for omnidirectional connections between starburst amacrine cells and directionally selective ganglion cells in rabbit retina, with associated bipolar cells, Visual Neurosci., 19, 145-162 (with journal cover illustration).
Famiglietti E.V. (1992) New metrics for analysis of dendritic branching patterns demonstrating similarities and differences in ON and ON-OFF directionally selective retinal ganglion cells, J. Comp. Neur., 324, 295-321.
Famiglietti E.V. (1992) Polyaxonal amacrine cells of rabbit retina: morphology and stratification of PA1 cells, J. Comp. Neur., 316, 391-405.
Famiglietti E. V. (1991) Synaptic organization of starburst amacrine cells in rabbit retina: Analysis of serial thin sections by electron microscopy and graphic reconstruction, J. Comp. Neur., 309, 40-70.
Famiglietti E.V. and Tumosa, N. (1987) Immunocytochemical staining of cholinergic amacrine cells in rabbit retina, Brain Res. 413, 398-403.
Famiglietti E.V. Jr. (1983a) "Starburst" amacrine cells and cholinergic neurons: mirror-symmetric ON and OFF amacrine cells of rabbit retina. Brain Res. 261, 138-144.
Famiglietti E.V. Jr. (1983b) On and Off pathways through amacrine cells in mammalian retina: the synaptic connections of "starburst" amacrine cells. Vision Res. 23, 1265-1279.
Famiglietti E.V. Jr. (1981) Functional architecture of cone bipolar cells in mammalian retina. Vision Res. 21, 1559-1563.
Vaughn J.E. Famiglietti E.V. Jr. Barber R.P. Saito K. Roberts E. and Ribak C.E. (1981) GABAergic amacrine cells in rat retina: immunocytochemical identification and synaptic connectivity. J. Comp. Neurol. 197, 113-127.
Nelson R. Famiglietti E.V. Jr. and Kolb H. (1978) Intracellular staining reveals different levels of stratification for On- and Off- center ganglion cells in cat retina. J. Neurophysiol., 41, 472-483.
Famiglietti E.V. Jr. Kaneko A. and Tachibana M. (1977) Neuronal architecture of ON and OFF pathways to ganglion cells in carp retina. Science 198, 1267-1268.
Famiglietti E.V. Jr. and Kolb H. (1976) Structural basis for ON- and OFF- center responses in retinal ganglion cells. Science 194, 193-195.
Famiglietti E.V. Jr. and Kolb H. (1975) A bistratified amacrine cell and synaptic circuitry in the inner plexiform layer of cat retina. Brain Res. 84, 293-300.
Kolb H. and Famiglietti E.V. Jr. (1974) Rod and cone pathways in the inner plexiform layer of cat retina. Science 186, 47-49.
Famiglietti E.V. Jr. (1970) Dendrodendritic synapses in the lateral geniculate nucleus of the cat. Brain Res. 20, 181-191.