Project Objectives

• Characterise early Fragile X syndrome (FXS)‑linked deficits in corticostriatal tripartite synapses.
• Develop deep‑learning pipelines to analyse synaptic structure.
• Perform scRNA‑seq and MERFISH to confirm affected cell types and developmental periods.
• Use confocal and STED imaging to assess dendritic spine morphology and astrocyte–neuron contacts.
• Publish an open‑source segmentation pipeline for reuse by other researchers.

3Rs Impact

• Replaces animal models with human‑derived assembloids.
• Refines research using computational analysis.
• Promotes broader uptake of organoid systems across neuroscience.
• Enables early‑stage disease investigation currently not possible in animal models.

Background

Fragile X syndrome (FXS) is a disorder associated with impaired nervous system development, resulting from a mutation in the FMR1 gene. It is a leading cause of autism, a prevalent neurodevelopmental condition that remains untreatable. FXS animal models show deficits at the level of neuronal connections, called synapses. However, other cell types are affected as well, such as astrocytes, which are glial cells required for proper neuronal connection and function. Despite this, astrocyte-synapse interactions, otherwise known as the tripartite synapse, remain underexplored in the developing human brain.

It has become easier to do so though, thanks to organoid and assembloid technologies, which allow us to model human‑specific brain development at the level of diverse neuronal and glial cell types, and inter‑region connections. These systems make it possible to examine molecular alterations, structural synapse defects, and astrocytic contributions in a human context. The research team will take advantage of this, and address the knowledge gaps surrounding early tripartite synapse pathology in Fragile X syndrome.