March 25 2011

Identification of key regulator of synapse plasticity and its role in enhancing memory

Two studies published this week in the renowned scientific journal Neuron from scientists from the Friedrich Miescher Institute for Biomedical Research (FMI) provide new insights on the mechanisms underlying synapse formation and elimination in the nervous system. They further dissect how these processes enhance memory formation and learning.

There are instances when our nervous system is a huge construction site. Structures are being torn down, new ones built. This happens first during the formation of the central nervous system during development and again, although to a lesser extent, while learning and forming memories. At these times, certain connections between nerve cells are being cut and others formed. As in the construction industry, the success of these endeavors strongly relies on the performance of the foreman conducting the works on site. In two publications published in Neuron this week, scientists from the Friedrich Miescher Institute for Biomedical Research (FMI) could show that, in the nervous system, ß-Adducin takes on the role of the foreman. In a first study, they identified Adducin as a key modulator of both synapse formation and stability and analyzed its regulation and interaction with the cytoskeleton. In the second study, FMI scientists determined the influence of ß-Adducin on learning and memory.

Control of synapse formation and maintenance
A team around the neurobiologist Jan Pielage from the FMI was interested in a better understanding of synapse formation and elimination in the neuromuscular junction of Drosophila. "So far no molecular mechanism was known to participate in these opposing activities," comments Pielage, "even though these processes need to be tightly regulated during the formation of the nervous system." In their study in Neuron, Pielage and his colleagues could show that the Drosophila version of Adducin, called Hts, controls two opposing processes during synapse remodeling. Through its interactions with the cytoskelatal protein actin, Hts/Adducin regulates the formation of synapses, through spectrin it stabilizes synapses. They could further show that synapse remodeling is sensitive to the Hts/Adducin levels in the synapses. These levels in turn are controlled through phosphorylation. "We think that Hts/Adducin with this dual function can define a switch between synapse stability and dynamics".

Enhancing learning and memory through Adducin
Pico Caroni, on the other hand, is interested in learning and memory processes in the hippocampus. Though it has been an established fact that synapse remodelling in the hippocampus is associated with learning and memory, a causal relationship has never been establish, mainly because the community lacked the tools to specifically interfere with synaptogenesis. "It has been a well established fact that providing animals with rich sensory, motor and social stimuli, increases the number of synapses in the brain and enhances learning and memory," comments Caroni. "By interfering with synapse formation in this setting, we hoped to causally link learning and memory formation with synaptogenesis." Based on this, the scientists analysed synapse remodelling and memory formation in the presence and absence of ß-Adducin, a protein already implicated to regulate plasticity and learning. Mice lacking ß-Adducin failed to form new synapses and their memory was impaired in the stimuli rich environment. The scientists could show that synapse remodeling and formation is critical for learning and memory in the adult, and that ß-Adducin is crucially important to establish the new synapses in situations when synapses need to be rearranged. "In the future, we aim to understand better how impairment of these processes may produce memory loss in diseases."

The power of model organisms
Taken together the two studies illustrate the power of using model organisms to explore complex mammalian functions, such as the brain. Here, fly genetics led to the identification of a protein that turns out to play a major role during memory formation and learning in the hippocampus of the mouse. "This is a beautiful example of how directly relevant findings in the fly are for complex processes in mammals. This is only one in a series of success stories of the fly in this field and it is the driving force for our research," comments Pielage.

Publications in Neuron
Pielage J, Bulat V, Zuchero B, Fetter RD, Davis DW. (2011). Hts/Adducin controls synaptic elaboration and elimination. Neuron 69:1114-1131

Bednarek E, Caroni P. (2011) ß-Adducin is required for stable assembly of new synapses and improved memory upon environmental enrichment. Neuron 69:1132-1146

More about Jan Pielage
Jan Pielage is a group leader at the FMI. He is interested in the processes involved in the proper development and function of neuronal circuits. In particular, he is interested in the regulatory mechanisms controlling formation and stability as well as synapse disassembly. He is using the Drosophila neuromuscular junction (NMJ) as a model system to understand these cellular and molecular mechanisms.
» More about Jan Pielage

More about Pico Caroni
Pico Caroni is a group leader at the FMI and Professor of Neurobiology at the University of Basel. He is interested in the mechanisms that control the formation, the maintenance and the turnover of synaptic connections in the brain, namely in the hippocampus. He has been a pioneer in understanding how these processes relate to learning, adaptation and memory and how they are impaired in disease.
» More about Pico Caroni

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