Nanodomains are involved in neuronal communication
Researchers use localization microscopy to observe microscopic changes in individual molecules in pre- and post-synapses
30 April 2020
It is the malleability of the human brain that enables us to learn and remember things. An important factor in this regard is synaptic plasticity, or the way that the transmission of stimuli from one nerve cell to the next can dynamically varied. Professor Martin Heine and his team at Johannes Gutenberg University Mainz (JGU) are investigating exactly how the exchange processes between the synapses work. "The properties of neuronal synapses are constantly changing – that is what we mean by synaptic plasticity," the biologist explained. In a joint article in Trends in Neurosciences co-authored by Dr. David Holcman, Research Director for Applied Mathematics and Computational Biology at the École normale supérieure in Paris, Heine has demonstrated how nanodomains contribute to the shaping of neuronal communication.
Localization microscopy makes movement visible
Synapses are the contact points through which nerve cells are able to communicate with each other. A single nerve cell can receive up to 30,000 synaptic messages from other nerve cells. The temporal and spatial sequence of the incoming signals determines the processing and transmission of information in the brain. At the contact points, incoming electrical impulses are converted into chemical signals and passed on to the next cell. Calcium ions first flow into the presynapse, i.e., into the upstream nerve cell that intends to emit a signal. This influx of calcium ions then leads to the release of messenger substances, known as neurotransmitters, which diffuse in the synaptic cleft and activate postsynaptic receptors. The dynamics of the molecules involved – which include voltage-gated calcium channels on the transmitter side and receptors for the neurotransmitters on the receiver side as well as synaptic adhesion molecules – are crucial to information transfer and synaptic plasticity.
These dynamics can be observed using localization microscopy by marking the molecules with a fluorescent tag and tracing them with the help of super-resolution microscopy as they move through living nerve cells. "We can even localize individual molecules, track their movements, and trace their pathways," Professor Martin Heine pointed out. Mathematical methods can then be used to ascertain how freely the molecules can move and to determine the density of the molecules present in the nanocompartments. "This means that we have the ability to observe extremely small changes in the distribution of individual molecules and to compare them with the synaptic activity." Since synapses are subject to constant growth and decay, receptors are constantly changing in their arrangement and density.
Nanoscale signaling molecules exhibit varying forms of organization
"Interestingly, the nanoscale organization of key effector molecules is highly heterogeneous," stated Heine and Holcman in their article entitled "Asymmetry between pre- and postsynaptic transient nanodomains shapes neuronal communication". The contact points in front of and behind the synaptic cleft each have a diameter of 200 to 500 nanometers – which is roughly the size of the smallest bacteria. In more concrete terms, the presynaptic calcium channels and postsynaptic ion channels, for example, such as the AMPA receptors where the neurotransmitter glutamate docks, are organized in nanodomains. A nanodomain is characterized by the density of the molecules present there. The denser they are at the location, the more their movement is restricted and the more difficult it becomes for these molecules to escape this nanodomain. There is a wide range of different interactions that can determine the length of time the molecules remain in a nanodomain. While both the pre- and postsynaptic nanodomains exhibit a high density of molecules, they differ significantly in the dwell time of the molecules – and this therefore has an influence on synaptic transmission.
Alternative splicing modifies the structure of calcium channels
In the future, Heine's team plans to continue to investigate calcium channels and the molecules associated with them. One phenomenon that is still very little understood is so-called alternative splicing, a process which can change the structure of molecules. Calcium channels are not immune to this process, and the results can be varying effects on short-term plasticity, as Heine's team has been able to demonstrate. Although they are undertaking what is essentially fundamental research, it is expected that a deeper understanding of the structure and function of calcium channels will be relevant also to the development of medical applications. "We assume that alternative splicing regulates the functioning of the channels on a cell-specific basis. It will be interesting to find out which factors trigger and control alternative splicing," said Heine.
From 2009 to 2018, Martin Heine headed the Molecular Physiology research group at the Leibniz Institute for Neurobiology in Magdeburg. In 2018, he was appointed Professor of Functional Neurobiology at JGU. His research group at Mainz University focuses on the role played by molecular dynamics of ion channels and adhesion molecules in synaptic plasticity and their contribution to neuronal network activity.