Enlightenment in the nervous system
A German-American team has modified nerve-cell receptors involved in regulating synaptic plasticity so that they react to light. The approach promises new insights into the basis of learning and the pathogenesis of neurological diseases.
Information processing and storage in the nervous system is mediated by specialized receptors that extend through the nerve-cell membrane. Many of these transmembrane proteins, including the “metabotropic” glutamate receptors (mGluRs), belong to the family of so-called G protein-coupled receptors (GPCRs). Activation of some types of mGluR reduces the excitability of nerve cells and inhibits the release of neurotransmitter. They also play a central role in “synaptic plasticity” by adjusting the strengths of the functional connections (synapses) between nerve cells depending on local patterns of activity.
Information flow in the nervous system depends on the efficiency of intercellular signal transmission, and synaptic plasticity is essential for memory storage, and thus for all forms of learning. Detailed knowledge of the processes that modulate signal transmission is therefore crucially important for an understanding of higher neural functions. Dirk Trauner, Professor of Chemical Biology and Genetics at LMU Munich, in collaboration with Professor Ehud Isacoff (University of California, Berkeley), has now been able to sensitize mGluRs to light, enabling researchers to regulate their activity on demand.
Trauner specializes in “retooling” receptors in this way. Using a combination of genetic engineering and chemical modification, he equips them with a switch that reacts to light of certain wavelengths. For instance, he recently reconfigured a transmembrane protein that binds the neurotransmitter acetylcholine in this fashion. In cooperation with colleagues in the US, he has now extended the approach to the mGluRs. Trauner explains the advantages of the method as follows: “Light can be controlled very precisely. With our constructs we can alter cellular states with high temporal and spatial resolution, and in a fully reversible fashion.”
Control with millisecond precision
Probably the best-known light-sensitive GPCR is rhodopsin, which is found in the retina and mediates vision. Unlike rhodopsin, Trauner’s optically controlled switch can be switched on and off very rapidly, within milliseconds. “This approach gives us the unique opportunity to elucidate the specific functions of every single type of receptor,” he says. This is particularly important in the case of mGluRs, because the same receptor protein can have diverse effects depending on the nature of the proteins with which it interacts.
The latest optical switch designed in Trauner’s laboratory has been shown to be functional when expressed in brain cells of the mouse, and in live zebrafish. In the latter, the researchers have used light flashes to show that mGluRs are involved in the control of the escape reflex that is activated when the fish encounter an obstacle. Activation of the artificial receptor by light alters the threshold at the escape reflex is triggered. The new findings are also of potential clinical interest, as the functions of GPCRs that respond to neurotransmitters are disturbed in many neurological syndromes.
The mGluRs offer interesting drug targets for the treatment of conditions such as depression and schizophrenia. ”We are still at the stage of basic research, but our mGluR could possibly find application in the therapy of certain disorders of vision, since the natural receptor is selectively expressed in certain cells in the retina,” says Trauner. (Nature Neuroscience 2013) göd