Behavioral Phenotypes of Foxg1 Heterozygous Mice

Authors: Skyler Younger, Sydney Boutros, Francesca Cargnin, Shin Jeon,, Jae W. Lee, Soo-Kyung Lee and Jacob Raber

Journal: Frontiers in Pharmacology, section Neuropharmacology.

Date: June 8, 2022

Abstract:

FOXG1 syndrome (FS, aka a congenital variant of Rett syndrome) is a recently defined rare and devastating neurodevelopmental disorder characterized by various symptoms, including severe intellectual disability, autistic features, involuntary, and continuous jerky movements, feeding problems, sleep disturbances, seizures, irritability, and excessive crying. FS results from mutations in a single allele of the FOXG1 gene, leading to impaired FOXG1 function. Therefore, in establishing mouse models for FS, it is important to test if heterozygous (HET) mutation in the Foxg1 gene, mimicking genotypes of the human FS individuals, also manifests phenotypes similar to their symptoms. We analyzed HET mice with a null mutation allele in a single copy of Foxg1, and found that they show various phenotypes resembling the symptoms of the human FS individuals. These include increased anxiety in the open field as well as impairment in object recognition, motor coordination, and fear learning and contextual and cued fear memory. Our results suggest that Foxg1 HET mice recapitulate at least some symptoms of the human FS individuals.

Significance:

This paper from Lee lab at University at Buffalo, conducted in collaboration with Jacob Raber’s group at Oregon Health & Science University, is the first comprehensive behavioral studies on Foxg1 heterozygous mice.  They found that Foxg1 heterozygous mice show various phenotypes resembling the symptoms of the human FOXG1 syndrome individuals.  Those include increased anxiety in the open field as well as impairment in object recognition, motor coordination, and fear learning and contextual and cued fear memory.  The results presented in this paper suggest that Foxg1 heterozygous mice recapitulate at least some symptoms of the human FOXG1 syndrome individuals.

However, it is important to note that the spectrum of symptoms widely differs among FOXG1 syndrome individuals depending on the type and location of the mutation in the FOXG1 gene, highlighting the need for patient-specific animal models and personalized therapeutic intervention for FOXG1 syndrome individuals.  Lee lab has also been developing a series of patient-specific mouse models.  Excitingly, their preliminary results reveal that those mouse models faithfully recapitulate various patient-specific symptoms. These new mouse models will serve as the fundamental platforms to study the etiology of the FOXG1 syndrome and for drug discovery.

Funding:

This work was partly supported by the FOXG1 Research Foundation, S-KL, and JL.