Could self-regulating synapses help us better understand Alzheimer’s?

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Could self-regulating synapses help us better understand Alzheimer’s?

6-Aug-2019

The University of Otago’s Dr Owen Jones never planned to come to New Zealand. Looking for adventure after completing a psychology and neuroscience degree at the University of Liverpool, he moved to Japan to teach English. There, he met a kiwi woman, “and you can probably guess the rest of the story,” Owen said, laughing. But since arriving in Dunedin in 2008, he’s established himself as an exciting early career researcher, thanks in part to the support of Brain Research New Zealand (BRNZ).

Owen’s introduction to Otago came in the form of a meeting with BRNZ Co-Director, Professor Cliff Abraham. “I got in touch with Cliff to discuss the possibility of doing my fourth year of study in his lab,” Owen said. “In hindsight, walking into his office that day was a stroke of good luck.” At the time, Cliff was leading an extensive research stream into how neurons form connections with one another, aiding in learning and memory, and how those connections become stronger or weaker. An emerging player in this research were glial cells, once thought to be no more than support structures for neurons. But researchers across the globe were beginning to view them differently; linking them to a range of neurological processes.

It was an exciting time to be a young neuroscience researcher, so Owen was thrilled when a year-long project turned into a PhD. Cliff and his team had been investigating signal messaging across neurons for some time, and according to Owen, “… we started wondering if there might be an intermediary cell involved in transferring signals from one side of the cell to the other.” Over the next four years, Owen and his colleagues determined that this was indeed the case, and showed that astrocytes (star-shaped glial cells) worked in partnership with neurons to regulate the strength of their connections. It proved to be a rich research vein – the team have published numerous papers on their astrocyte work, and have more to come.

For Owen, though, this research triggered a new interest, “I wanted to look at longer-term processes. Specifically, at how and why prolonged changes in brain activity can drive chronic changes at synapses; the connections between neurons.” Collectively, these processes are referred to as homeostatic plasticity, and the basic concept is that neurons have the ability to regulate their own activity. In other words, if brain cells are chronically over-active, neurons will react by weakening all of their connections to bring the overall firing rate back down to an optimal level. The inverse is also true, but Owen was fascinated by this particular form of neural plasticity – homeostatic synaptic downscaling – and its potential link to the progression of neurodegenerative diseases.

This work marked a point of departure from his PhD research, but luckily, it coincided with the launch of BRNZ’s postdoctoral fellowship programme. “The BRNZ fellowship was a golden opportunity which I was so lucky to get” said Owen, “It allowed me to set up a new research stream, and gave me the space to start striking out on my own.” Key to the success of Owen’s fellowship research was the support he received from Prof Cliff Abraham and Prof Ruth Empson – he describes them both as “…fantastic mentors, especially as I’ve been trying to establish myself a bit more independently. They’ve seen and done it all, and have both published lots of very high impact papers. But the thing I’ve most appreciated has been their patience!”

Owen put that support to good use. During those two years, he found that the Alzheimer’s-related protein Tau seems to play a critical role in mediating homeostatic synaptic downscaling. This finding attracted the attention of a group at Huazhong University of Science and Technology in China, and has led to Owen’s first international collaboration. In a project, co-funded by the HRC and National Natural Science Foundation of China, they’ll build on work done at both Otago and Huazhong, and take it further, “We already know that Alzheimer’s is a disease that affects our memories and ability to learn, and at a biological level that synapses fail to get stronger,” Owen said. “But I’m beginning to wonder if that’s only part of the story; rather than synapses just being unable to get stronger, it may also be that homeostatic downscaling causes them to actively weaken.”

To explore this idea, Owen will be working with a number of BRNZ researchers, including Associate Professor Joanna Williams, and Associate Professor Ping Liu. And while the focus is on Alzheimer’s disease, Owen believes his results may have wider implications too. “Tau deposition is also a hallmark of Parkinson’s and Huntington’s diseases, and is seen in temporal lobe epilepsy,” he explained. “It’s possible that homeostatic plasticity mechanisms could contribute more to disease than we think.”

– Written by Laurie Winkless