New optical tools for controlling neuronal activity
Introduction
In cells, light is used for two main purposes: first, to produce energy through photosynthesis; and second, to couple extracellular stimuli to intracellular signaling pathways, such as enzymes, ion transporters or ion channels. The second use is particularly interesting to us because switching on and off ion transporters, ion channels or second messenger pathways by light provides an opportunity to control non-invasively the membrane potentials and second messenger cascades in a living animal. Recently, it has been demonstrated that neuronal circuits can be manipulated through the exogenous expression of mutated ion channels and G-protein-coupled receptors (GPCRs). Here we review recent progress made in this area and discuss the specific shortcomings of some of the methods proposed.
Section snippets
Visual system GPCRs for slow control of nerve cell activity
In the visual system of invertebrates and vertebrates, light of different frequencies can activate a molecular cascade leading to the depolarization of a nerve cell in invertebrates or the hyperpolarization of a nerve cell in vertebrates.
Ion channels for rapid control of nerve cell activity
Activation and deactivation of GIRK channels by pertussis toxin (PTX)-sensitive G proteins in neurons occur within one to several seconds. By contrast, ligand-gated and voltage-gated ion channels can be activated within microseconds, making the direct gating of ion channels the tool of choice for rapid control of nerve cell activity. The regional expression of a genetically modified K+ channel in Drosophila provided the first example of using an ion channel to control the excitability of the
Light-activated switches in physiologically relevant neuronal networks
So far three different light-activated proteins have been used to control neuronal circuits in intact tissue and live animals.
Application of light-activated ligands: the cell helps itself
Light-activated receptors or channels require the application and regeneration of a light-sensitive ligand to activate the receptor, which can be a problem for approaches that use synthesized compounds. The receptors have to be loaded before the experiment with a compound that has the potential to induce toxicity depending on the length of application and the compound itself. Fortunately, by using retinal-derived ligands, the cellular environment seems to help itself by providing the receptor
Conclusions
Controlling cellular signaling by light using light-activated switches has great potential for understanding basic cellular mechanisms and to elucidate how these mechanisms influence and determine system function and animal behavior. Several studies in Drosophila, C. elegans, chicken and mice have revealed the feasibility of the approach. In addition, development of light-activated molecular machines will have important implications for curing disease. For example, controlling ion conductance
Update
Recent work has also described the application of ChR2 in Drosophila larvae to determine whether defined neuronal circuits can distinguish between appetitive or aversive learning [44]. Pairing of odor stimuli, which were either appetitive or aversive, with a second neutral stimuli (fructose) led to an odor specific behavior. Expression and activation of ChR2 either in octopaminergic or dopaminergic neurons during application of the odors could substitute for fructose, suggesting that
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We thank Davina Gutierrez for reading the manuscript. This work was supported by grants from the National Institutes of Health (NS447752 and NS42623 to SH, and NS19640 and NS23678 to LTL).
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