Understanding neuronal function in brain-based diseases

University of British Columbia PhD candidate Hong Lu has been awarded the Shireen and Edna Marcus Award for his work in discovering a process essential to brain synapse development, in the hope of having a better understanding of the neuronal mechanisms in autism.

The human brain is made up of approximately 86 billion neurons, many of which have different properties. For example, some release excitatory signals that will make other neurons fire while others release inhibitory signals to stop other neurons from firing. The large variety of neuron types present in the brain is crucial to the expression of complex behaviours, and the properties of a structure called the synapse, which enables communication between neighbouring neurons, determine how a neuron transmits information and organizes into circuits with other nerve cells. Synapses that develop in an unusual way will lead to altered neuronal function, which can in turn lead to complex neuropsychiatric disorders such as schizophrenia and autism spectrum disorder (ASD).

“Hong Lu’s dedication to unlocking the mysteries of autism is inspiring and will certainly lead to innovation when it comes to preventing, diagnosing and treating the disorder.” – Viviane Poupon, President and CEO at Brain Canada

Hong Lu is one of two recipients of Brain Canada’s 2021 Shireen and Edna Marcus Excellence Awards. Lu is completing his PhD at the University of British Columbia under the supervision of Ann Marie Craig, whose lab has discovered a process essential to proper synapse development. The $4,500 award supports the recipient’s academic development and research into ASD.

Funding for the Shireen and Edna Marcus Excellence Award is thanks to the Shireen and Edna Marcus Foundation, a charity focused on supporting Canadian institutions and registered charities  conducting or assisting research in the prevention or treatment of autism. It has supported Brain Canada’s student awards since 2019.

“Hong Lu’s dedication to unlocking the mysteries of autism is inspiring and will certainly lead to innovation when it comes to preventing, diagnosing and treating the disorder,” says Dr. Viviane Poupon, President and CEO at Brain Canada.

For this project, the research focuses on neurexins, a group of 3 genes that give rise to proteins that sit on one side of the synapse, called the pre-synaptic side, and interact with proteins on the other side of the synapse, the post-synaptic side, to help neurons bind together and determine the properties of the synapse. One of these neurexins, neurexin-1, is of particular interest because a growing body of evidence indicates that some patients with schizophrenia and ASD are missing one of the two copies of the neurexin-1 gene normally present in DNA. In fact, the Simons Foundation Autism Research Initiative’s gene database, a tool for the autism research community that identifies genes implicated in autism susceptibility, lists neurexin-1 as one of the top risk genes for ASD.

As part of a team led by Peng Zhang, Hong found that modification of neurexin-1 by addition of a rare glycan, heparan sulfate, is essential for synaptic structure and function. Heparan sulfate modification controls binding of neurexins to multiple postsynaptic ligands. Hong is now studying mice with specific mutations in neurexin-1 to model ASD and to test a new therapeutic direction leveraging these recent findings. Hong’s goal is to alleviate deficits resulting from loss of one copy of the neurexin-1 gene by boosting the function of the remaining neurexin-1. Using a technique called electrophysiology which allows one to record the activity levels of individual neurons, Hong’s preliminary data supports this hypothesis, showing that this targeted approach could effectively restore neuronal function to normal.

Going forward, Hong wants to validate these results by looking at what happens at the level of the actual brain structures. He will do this first by using a technique called 3D electron microscopy, which will allow him to see detailed features of the synapses. He will then use a newer technique called expansion microscopy, where brain tissue is incubated in chemicals that make it transparent and expand the tissue by as much as 64 times. This technique will allow him to look at the molecular composition of brain synapses, something that has never been done before in these ASD models. In parallel, Hong’s team is also working with Richard Brown’s lab and PhD student Kyle Roddick at Dalhousie University to assess the behaviour of the different mouse models. The group hopes that any autism-like or schizophrenia-like behaviours will also be rescued by the targeted approach.

Though a lot of work remains to be done to fully understand what happens when the effectiveness of neurexin-1 is altered, Hong hopes that this project will help us better understand the neuronal mechanisms in autism. Ultimately, his research could also lead to treatments that could help alleviate the neuronal defects seen in some neuropsychiatric disorders, adding to the repertoire of tools available to help patients.

To learn more about this project and the wide range of research supported by Brain Canada, visit the directory of funded researchers: www.braincanada.ca/directory-funded-grants.