INSIDE THE LAB
With RSO-Funded Researcher Dr. Michaela Fagiolini
Dr. Fagiolini is studying how neurons in the cortex of the brain change during the onset and progression of Rett syndrome and how they change in response to Ketamine treatment. The cortex is the area of the brain that receives sensory information – sight, taste, smell, sound and touch. Rett syndrome alters the way the neurons process this sensory information.
Ketamine is a drug that has been used to treat other disorders and is being studied as a potential treatment for Rett syndrome. Dr. Fagiolini’s work will help lay the groundwork to determine proper ketamine dosing and help set parameters to evaluate ketamine’s effectiveness in Rett syndrome.
Dr. Fagiolini will image the brains of RTT mice as they respond to visual sensory information. She will compare the changes at the onset of RTT to changes after regression from RTT has begun. She will then image the brains after ketamine dosing to see its effect. This information will be used to determine the optimal dosage needed to re-establish proper function of neurons in the cortex. This work is being done on female RTT mice with a Mecp2 mutation. These mice have symptoms similar to the human condition. Because of this, Dr. Fagiolini says that the outcomes from this study will be immediately translated in the clinical setting and will help shape upcoming clinical trials.
Dr. Fagiolini’s goal is to see how the RTT brain responds to sensory input from the environment, giving a better understanding of how abnormalities in the neuron networks of the cortex can be corrected. They will also measure the effectiveness of ketamine intervention on those networks, and determine the optimal dosage needed to re-establish proper function.
This will pave the way for the development of future ketamine clinical trials and additional treatments for Rett syndrome.
The Answers to your Questions
Our work –although conducted in our small little mouse patients – can be immediately translated into clinical settings. Indeed, clinical trials testing ketamine are in the making. This research is essential to develop proper outcome measures and proper dosing for those clinical trials.
Enrolling in the Natural History Study is the best way to help. Through the NHS, we can collect EEG and evoked potential (auditory and visual) data from those first diagnosed to those in adulthood. That information can be used to develop future clinical trials. Rett syndrome patients and their extraordinary families are our support and motivational system. We work for them to find a treatment and maybe one day a cure for these incredible children and adults with RTT.
Our work will help design a more effective clinical trial that hopefully will treat Rett syndrome and significantly improve their quality of life.
In December of 2019 we will have completed our study. We will share any progress made along the way with the Rett community.
Dr. Michela Fagiolini is an Associate Professor in the Department of Neurology at Boston Children’s Hospital, where she had launched her research on neurodevelopmental disorders and in particular Rett Syndrome. Her laboratory has an active collaboration with the Boston Rett Syndrome clinic and the laboratory of Cognitive Neuroscience.
Dr. Michela Fagiolini was awarded a Basic Research Award for the project “Two-photon imaging of excitatory/inhibitory cortical activity in mosaic Mecp2 female animal model”. To better understand what is happening inside the lab, we answer some common questions about this research below.
Two-photon imaging is simply a type of imaging that is ideal for visualizing the activity of distinct neurons in brain tissue of a living animal.
In a brain and working nervous system, there are two activities required: excitation and inhibition. Excitatory signaling from one cell to the next makes the latter cell more likely to fire. Inhibitory signaling makes the latter cell less likely to fire. The balance between neural excitation and neural inhibition is crucial to healthy cognition and behavior. In Rett syndrome, it has been thought there is in an imbalance in these activities due to loss of MeCP2 protein, which regulates both brain development and maintenance. Dr. Fagiolini is looking specifically at the cortical region – the visual cortex (a part of the cerebral cortex that processes visual information).
The goal at the end of the two-year project
Dr. Fagiolini and her lab hope to have a better understanding of how the expression or absence of MeCP2 impacts the neuronal activity of excitatory or inhibitory cortical circuits during regression and recovery in the visual cortex of RTT female mice. The experiment proposed here will allow them to directly visualize how brain cells are expressing or lacking MeCP2 change their ability to communicate and properly function during the progression of the disorder. They will also be able to understand better how pharmacological or genetic interventions affect the neurons and their ability to recover and to what degree.
For the scientific abstract of this project, click here.