A German-French team has developed a light-sensitive switch to regulate a protein involved in the neurobiology of synaptic plasticity. The agent could shed new light on the phenomenology of learning, memory and neurodegeneration, according to an article in Drug Discovery & Development
Learning is a result of functional connections between nerve cells in the brain that are subject to constant remodeling. Because of activation-dependent modification of these links (“synaptic plasticity”), circuits that are stimulated repeatedly "learn" to transmit signals more efficiently. This provides the molecular basis for learning and memory, enabling the information encoded in such networks to be recalled and exploited in novel situations. Specialized receptor proteins in nerve-cell membranes that mediate the transmission of electrical signals between individual neurons are the primary targets for modification.
A team of researchers led by Dirk Trauner, Professor of Chemical Biology and Genetics at Ludwig Maximilians-Universitat Munchen (LMU)
, in collaboration with colleagues at the Institut Pasteur in Paris, has now synthesized a light-dependent switch to control the activity of a class of receptors critical to the formation and storage of memories. The compound gives researchers interested in probing short- and long=term memory mechanism a new tool. The results appear in the online journal Nature Communications.
Individual nerve cells usually use chemical messengers to communicate with each other. These neurotransmitters are released by synapses at the end of the axon and diffuse across the synaptic cleft, and the chemical binds to receptors on the "post-synaptic" neuron. How the post-synaptic cell reacts depends on the nature of the neurotransmitter and the receptor.
According to Laura Laprell, a PhD student in Trauner's group and joint first author of the new study, "In this context, the so-called NMDA receptor is very special. It is primarily responsible for the fact that we have the capacity to form memories and the ability to learn."
Trauner and his colleagues have synthesized a chemical, azobenzene-triazole-glutamate (ATG), which acts as a light-sensitive neurotransmitter on NMDA receptors. Using this tool, it is now possible to activate and inactivate these receptors with high specificity and precision in the laboratory. Unlike other optical switches, ATG does not permanently bind to the receptor; it diffuses freely in the synaptic cleft between pre- and post-synaptic neurons.
Laprell explains, "ATG is completely inactive in the dark and must be exposed to light before it can bind to the receptor and initiate depolarization of the post-synaptic cell." Subsequent irradiation with UV light inactivates ATG in milliseconds, enabling precise control of receptor activation in the time domain.
The researchers expect to derive new insights into the mechanisms underlying synaptic plasticity and memory formation, as well as neurodegenerative diseases such as Alzheimer's and Parkinson's.