New Fragile X Syndrome research to study microglial influence and potential therapies

Dr. Brian Christie and Dr. Marie-Ève Tremblay (Division of Medical Sciences) have received a $40,000 USD grant from the FRAXA Research Foundation for their research on how microglia contribute to newly developed therapies for Fragile X Syndrome (FXS), the most common form of genetically inherited intellectual disability and a leading cause of autism spectrum disorder.

FXS is caused by a mutation of the Fmr1 gene on the X chromosome that leads to the loss of fragile X mental retardation protein (FMRP). Patients with FXS usually present deficits in cognition, language, sensory integration, and emotional responses as FMRP controls the translation of several proteins critical for synaptic function.

Previously, the Christie lab investigated several promising lines of treatment that enhance dendritic growth and restore synaptic function in the FXS brain. Specifically, these therapies revolve around enhancing the function of specific protein kinases called AMPKs. The lab recently focused on adiponectin, an endogenous AMPK activator that has the potential to restore synaptic and cognitive deficits. Understanding the mechanisms involved brought Dr. Tremblay, with her expertise in microglial involvement in synaptic remodeling, to the project.

Filopodia are an immature form of synaptic spines that are prevalent on neuron dendrites during fetal brain development. They are essential to the formation of new inter-neuronal connections and are the starting points for the brain’s functional meshwork. Each filopodia in the developing brain represents a potential connection between two neurons and, more broadly, the potential for the brain to learn or reinforce something new. Thus, it is important to tightly regulate the number of filopodia in the brain. Having too few or too many can negatively impact the way that signals are produced and received by neurons. This imbalance can impair the development of cognitive function, promote neurological decline, and contribute to disorders like epilepsy and FXS.

Dr. Tremblay brings an expertise in microglia to the project that can help determine how microglia, the resident macrophage cells of the brain, might regulate the number of filopodia. They do so by “chewing” away excess synaptic connections through a specialized and selective form of phagocytosis (similar to autophagy, but directed towards external cellular elements) called trogocytosis. Dr. Tremblay and Dr. Christie hypothesize that filopodia are not effectively eliminated by microglia in the FXS brain.

Irene Shkolnikov (MSc student, Neuroscience Graduate Program) will use the expertise of both laboratories to examine a role for microglia in FXS. Her research will also focus on two therapies under investigation in the Christie laboratory, Adiporon and Metformin. With Dr. Tremblay, she will explore if these compounds can enhance microglial form and markers of microglial function, including pruning action. This work will help clarify the improvements in synaptic function and behavioural performance already being observed with other AMPK activators by Christie lab post-doctoral fellows Dr. Luis Bettio and Dr. Jon Thacker (whose work was previously funded by FRAXA, the Fragile-X Research Foundation of Canada, and CIHR).