Steven F. Stasheff, MD, PhD
Research Profile
Contact Information:
UI Hospitals and Clinics
Department of Pediatrics
2506 John Colloton Pavilion
Office: 319-356-7726
E-mail: steven-stasheff@uiowa.edu
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My research interests center on the fundamental physiologic mechanisms of neurologic diseases affecting the visual system, and on the role that central
nervous system (CNS) plasticity may play in both the pathogenesis and potential treatments for such disorders. Ongoing investigations aim to better
understand electrophysiologic changes that occur in hereditary retinal degeneration, the most common inherited cause of blindness, and also a central
feature of many neurodegenerative disorders in children and adults, including those that cause severe mental retardation, motor disability, and seizures.
Currently proposed therapies for these disorders hinge upon the assumption that even after photoreceptor degeneration, remaining retinal neurons would be able
to normally process signals from rescued or replaced photoreceptors, or from direct electrical stimulation. In fact, significant anatomic reorganization of
the inner retina occurs, and recent work in my laboratory has identified corresponding physiologic changes that may involve mechanisms of developmental plasticity.
The lab uses state-of-the-art multielectrode recording to monitor spontaneous and light-evoked activity simultaneously from 30-90 retinal ganglion cells in normal
(wild type, wt) mice or those of the well-studied rd1 mouse model of retinal degeneration. Surprisingly, as the animal becomes blind, retinal ganglion cells do
not simply drift into silence as might be expected. Rather, they develop striking hyperactivity (~10 times normal firing rate) that is sustained for many weeks.
In fact, ganglion cells pass through at least three stages of activity: 1) normal spontaneous "waves" of correlated firing in early development; 2) increasing
spontaneous activity with temporary preservation of light-evoked responses, selective for the OFF pathway; then 3) sustained hyperactivity that lasts for months,
well beyond the loss of virtually all photoreceptors and light-evoked responses.
These striking alterations in inner retinal physiology tell us that in the rd1 mouse:
- blindness occurs in the face of sustained ganglion cell hyperactivity
- these cells remain viable, thus amenable to various treatments, for an extended time despite this activity;
- ON and OFF responses are differentially affected in early stages of degeneration.
Since photoreceptor loss begins early and progresses rapidly in rd1 mice, it overlaps substantially with a normal developmental period of highly active synaptic plasticity.
Thus, the lab now is comparing several transgenic mouse lines to explore the possibility that developmental plasticity may play an adaptive role in resculpting specific
inner retinal circuits such as the ON and OFF pathways. Other avenues of investigation include dissecting changes in the neural code that rd1 ganglion cells use to communicate
with the brain, exploring circuit-level and cellular mechanisms that underlie the alterations in their physiologic activity, and determining how widespread these changes are
among other neurodegenerative diseases such as neuronal ceroid lipofuscinosis (NCL) and tuberous sclerosis (TS).
Lab Members:
- Michael P. Andrews, BS, MBA
- Erik Nylen
- Tyson Kinnick, PhD
Affiliations:
Model System:
In vitro mouse and rabbit retina
Multielectrode and patch clamp recording
Recent Publications:
- Stasheff, SF. Emergence of sustained spontaneous hyperactivity and
temporary preservation of OFF responses in ganglion cells of the retinal
degeneration (rd1) mouse. (in press, J. Neurophysiol. 2008).
- Murtha, TJ and Stasheff, SF. Visual Dysfunction in Retinal and Optic
Nerve Disease. Neurology Clinics of North America 2003; 21: 445-481.
- Stasheff SF and Masland RH. Functional Inhibition in Direction Selective
Retinal Ganglion Cells: Spatiotemporal Extent and Intralaminar
Interactions. J. Neurophysiol. 2002; 88: 1026-1039.
- Jeon C-J, Kong J-H, Strettoi E, Rockhill R, Stasheff SF, Masland
RH. The Pattern of Synaptic Excitation and Inhibition Upon Direction
Selective Retinal Ganglion Cells. J. Comp. Neurol. 2002; 449: 195-205.
- Stasheff, SF and Barton, JJS. Deficits in Cortical Visual Function.
Ophthalmology Clinics of North America 2001; 14(1): 217-242.
- Ryan MM, Stasheff SF, Engle EC. Disorders of the Ocular Motor Cranial
Nerves and Extraocular Muscles. In: Jones, Jr HR, De Vivo D, Darras BT, eds. Neuromuscular Disease of Infancy and Childhood: A Clinician’s
Approach. Woburn, MA: Butterworth-Heinemann, 2002.
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