Grant: Project Grant

The ATRX gene codes for a protein critical for brain function. ATRX stands for Alpha-Thalassemia/Mental Retardation Syndrome X-Linked, which is linked to a genetic disorder affecting brain development. The ATRX protein helps regulate how genetic information is read and maintained in brain cells by interacting with DNA and chromatin (the material that makes up chromosomes). It controls the expression of several genes necessary for brain development and function. When ATRX is dysfunctional, it therefore leads to abnormal brain development and cognitive impairments, particularly intellectual disabilities and autism spectrum disorders. To study the role of ATRX, we generated a mouse that has been genetically altered so that the ATRX gene has been "turned off" or "knocked out." This mouse does not produce the ATRX protein, similar to people with ATRX mutations where the protein does not function properly. Using this model, we found that the fine structure of the hippocampus, a region of the brain essential for memory and learning, was altered. Moreover, these mice performed poorly in a navigation task, reflecting cognitive deficits. How this occurs, however, is unclear. We propose to carry out a very specific set of experiments to determine with high precision how the function of the hippocampus is altered in these mice. We will conduct electrical recordings of neurons and synapses in these mice in vitro, simultaneously with microscopy-based optical imaging of several aspects of neuronal signaling. We will also carry out recordings from hippocampal neurons while these mice are navigating in a maze or in a virtual reality environment. These experiments will allow us to identify with unprecedented precision the synaptic and network underpinnings of the behavioral manifestations of ATRX dysfunction. We hope that this new knowledge will help the field develop therapeutic or management strategies to support individuals with learning and intellectual disabilities.