Functional and Genomic Characterization of Interneurons in the Fmr1-KO Mouse Brain
Principal Investigator
FRAXA Fellow
France
Summary
The brain’s balance is maintained by two types of neurons: those that excite and those that inhibit activity. Like yin and yang, this balance is essential.
This team has found fewer than normal inhibitory cells in the brains of Fragile X mice. They are now working to pinpoint this abnormality and find ways to restore the normal balance and function.
The Science
By Barbara Bardoni, PhD
The brain has many different kinds of cells, but these can be broadly divided into neurons (electrically active cells) and glial (supporting cells which do not participate directly in neurotransmission.) Neurons can be further subdivided into excitatory and inhibitory neurons. The latter ones are called interneurons and different types of interneurons express different marker proteins and each has a different embryological origin.
It is thought that an imbalance of excitatory and inhibitory activity is a hallmark of neurodevelopmental disorders. This imbalance is also seen in Fragile X syndrome (FXS); indeed, it is characterized by a neuronal hyperexcitability and decreased interneuron activity.
We set up a technique called agonist-induced functional analysis (aiFACS) allowing us to isolate interneurons from young Fragile X mouse brains on the basis of their response to neurotransmitters, and then conduct genomic analysis at the single-cell level. We observed a reduced number of cells belonging to the 5HT3aR interneurons class among FXS interneurons compared to control cells. This indicates that this subclass of inhibitory neurons contributes to the alteration of the excitatory/inhibitory balance in FXS brains.
Our project will continue in this direction, by studying the response of FXS interneurons to various stimuli induced by several neurotransmitters such as GABA, Glutamate, Dopamine, Serotonin.
The aim of our study is two-fold:
- To better understand the deficits of the different classes and sub-classes of interneurons in FXS, which is key for understanding the pathophysiology of the disorder;
- To set up the conditions for a future cell replacement therapy using interneurons in FXS. This technology has already been proposed to treat different brain disorders, in particular, some forms of epilepsy.
In summary, our approach will allow us to define new sub-classes of defective interneurons in FXS. A therapeutic approach based on cell replacement should be more effective if it targets only the defective sub-classes of cells. This approach should also enhance the effectiveness of cell replacement therapies in other brain disorders.
