October 30, 2008 |
by Warren Grill, senior technical editor and James Cavuoto, editor
October 30, 2008
One of the most promising new areas of neurotechnology research involves a combination of optical stimulation with genetic engineering techniques to “manufacture” light-sensitive neurons that can be activated without the need for implanted electrodes [NBR Jan07 p1]. These approaches use genetically controlled exogenous expression of chromophore-linked ion channels that confer light sensitivity to neurons not normally responsive to light.
These optogenetic tools offer the promise of highly selective stimulation of targeted cells—both temporally and spatially—and may form the basis of a new generation of neurotechnology solutions to neurological disease and injury. The first commercial endeavor exploiting these techniques was recently launched in southern California. And two recent publications highlight the application of light-activated channels to treat blindness resulting from photoreceptor loss, as occurs in retinitis pigmentosa and macular degeneration.
Pamela Lagali and colleagues from the Friedrich Miescher Institute for Biomedical Research, in Basel, Switzerland, and Connie Cepko at Harvard Medical School expressed the algal protein channel rhodopsin-2, a chromophore linked to a cation-permeable transmembrane channel, in ON type retinal bipolar cells. Publishing in Nature Neuroscience, they demonstrate that ChR2 expression in a mouse model of photoreceptor loss allowed light to evoke action potentials in retinal ganglion cells, via synaptic connection from the bipolar cells.
The light-evoked activity was propagated through the visual system, and flash-evoked responses in visual cortex were similar in treated and normal mice, whereas no response was present in untreated mice with degenerated photoreceptors. As well, treated mice exhibited behavioral evidence of light perceptions including increased locomotor activity in a bright environment and visual following of moving gratings.
Similarly, Lin and colleagues from the Massachusetts General Hospital and The Salk Institute reported in the Proceedings of the National Academy of Sciences on the restoration of visual function by exogenous expression of the light-sensitive protein melanopsin in retinal ganglion cells in a mouse model of photoreceptor loss. Light activation of melanopsin leads to opening of a membrane channel and generation of action potentials.
Virally mediated gene transfer increased almost ten-fold the number of retinal ganglion cells expressing melanopsin, and the exogenous expression imparted light sensitivity to the retinal ganglion cells. Further, the treated mice exhibited normalized pupillary response to light and improved behavioral performance on two tasks requiring light from dark discrimination. Although none of the behavioral tasks required temporal or spatial resolution, they do demonstrate the feasibility of functional improvement in vision using these approaches.
These studies represent substantial advances in the application of light-sensitive channels for restoration of function. However, there remain several challenges before this is likely to displace retinal electrical stimulation as a promising form of restoration of vision in persons blind from loss of photoreceptors.
ChR2 is an algal protein and might prompt an adverse immune response during long-term expression. Further, activation of ChR2 requires very high light intensities, and it might not be suitable for vision under ambient conditions. Melanopsin is normally engaged in circadian signaling, and the slow onset and persistence of responses generated by ectopic melanopsin may limit the temporal resolution of visual percepts. The response of retinal ganglion cells to a very brief (1 sec) light stimulus exhibited latencies up to several seconds and prolonged responses lasting over one minute after the initial stimulus. Nonetheless, these recent advances highlight the promise of optogenetic approaches to neural control and rehabilitation.
A southern California startup firm called EOS Neuroscience hopes to be the first to commercialize these techniques. Founded by Alan Horsager, a neurosciences Ph.D. candidate at University of Southern California and MIT grad Ben Matteo, the firm recently won a $36,000 prize from USC’s Biomimetic MicroElectronic Systems Engineering Research Center. They plan to license technology developed at Karl Deisseroth’s lab at Stanford University.
