Exploring the Role of Microglia in Fragile X Syndrome Using an in Vivo Human Induced Pluripotent Stem Cell-Based Model
Marine Anais Krzisch, PhD
Principal Investigator
University of Leeds
United Kingdom
2025 Grant Funding: $35,000
Co-Funded with the Autism Science Foundation
Summary
FRAXA and the Autism Science Foundation are funding a project which explores a new piece of the Fragile X puzzle — microglia, the brain’s immune support cells.
While most Fragile X Syndrome research has focused on neurons (the brain’s communication cells), microglia are increasingly recognized as critical players in brain development and health. They help shape brain circuits and clear out damaged cells — and if they're not functioning properly, they could contribute to brain dysfunction in Fragile X. Dr. Krzisch is using a cutting-edge approach that involves transplanting human microglia, made from patient-derived stem cells, into the brains of mice. Dr. Krzisch will study how Fragile X microglia behave in a living brain and hopefully uncover new pathways to treatment.
Exploring Microglia as a Therapeutic Target – with Dr. Krzisch and Dr. Tranfaglia
In this podcast, Dr. Marine Krzisch (University of Leeds) and Dr. Mike Tranfaglia (FRAXA Research Foundation) explore how targeting microglia could open the door to new treatment strategies. They discuss recent breakthroughs, why microglia matter, and how this innovative approach could benefit individuals with Fragile X and related conditions.
The Science
by Dr. Marine Krzisch
I aim to understand the biological reasons behind profound autism, by studying microglia, a type of brain cell, and their impact on neurons. My focus is on Fragile X syndrome (FXS), a major genetic cause of autism.
Microglia remove connections between neurons, called synapses, during brain development. This is called synaptic pruning. Dendritic spines are small protrusions on the branches of neurons that correspond to a type of synapse. Dendritic spines are more numerous and thinner in FXS patients’ brains.
I hypothesize that:
- defective synaptic pruning by FXS microglia contributes to the dendritic spine abnormalities
- FXS microglia have an increased inflammatory response
- This affects neuronal health and function
To test my hypotheses, I will use an innovative model, where I transplant human microglia into the mouse brain. This model is necessary as mouse models of FXS do not accurately reflect the human condition, and cultured human cells lack the complexity of a whole brain. Transplanting human microglia into a mouse brain provides a more accurate model as it allows these cells to develop in a living brain.
This research will enhance our understanding of the anomalies in microglia in FXS. This is likely to be helpful to many other forms of profound autism, as abnormal microglia have been found in these disorders too. It may pave the way for developing new therapies for profound autism. In future research, I will apply these methods to other autism risk factors, to uncover common mechanisms in autism spectrum disorders
Meet the Scientist
Dr. Marine Krzisch is a neuroscientist with a deep focus on disease modeling using human stem cell-derived brain cells. She trained as a postdoctoral fellow in the MIT laboratory of Dr. Rudolf Jaenisch, one of the pioneers of stem cell research, before launching her own lab at the University of Leeds in the UK.
Dr. Krzisch brings a uniquely translational approach to Fragile X research, using cutting-edge humanized models to better understand microglial behavior and synaptic development. Her passion for science is rooted in a desire to improve lives through targeted therapies, especially for complex neurological and developmental conditions.
