Mouse Models Used In Treating Rett Syndrome

Mouse Models Used In Treating Rett Syndrome

Mouse Models with an Impaired MECP2 Gene Lead to Breakthrough in Treating the Rett Syndrome

Unlike most neurodevelopmental disorders, the Rett syndrome can be traced to the failure of a specific gene known as MECP2. As a team of researchers at Cold Spring Harbor Laboratory (CSHL) have experimented with mouse models carrying the syndrome, they have discovered how failure and mutations in the mouse equivalent of the MECP2 gene has led to biological impairment later in the life of the mice, with adult females, for example, being unable to learn how to carry newborn pups. The CHSL research is supported by the SFARI, the International Rett Syndrome Foundation and the National Institute of Mental Health, and was initially published on January 18, 2017 in Nature Communications.

Adult Plasticity and MECP2 Mutations

The research is led by Professor Stephen Shea, who considers the study of females’ behavior to be one of the best ways of testing the changes brought about by MECP2 mutations. Billy Lau, Ph.D. and Keerthi Krishnan, Ph.D. have performed much of the work at CSHL, and consider the experiment to be one of the first steps in explaining the long term effects of the Rett syndrome on the development of adult females.

Detailed comparisons were made between the learning abilities of healthy female mice and mouse models with MECP2 gene mutations. It was established that the inability to learn had its source in a number of failures at a molecular level, with affected females experiencing abnormal neural plasticity upon the synthesis of a neurotransmitter called GABA. PV+ neurons seem to play a vital role in this process by expressing unusually high levels of the parvalbumin signaling protein. This has led to the inability of the females to learn their normal behavior, commonly triggered by the pups’ squeals.

The problem mainly appears in the auditory cortex, where the perineuronal nets that support PB+neurons are impaired, so that the neurons become unable to form synaptic connections with other neurons and promote experience-based learning.

Learning Restored

The discovered impairments have provided researchers with a great deal of information about the impact of a defective MECP2 gene on the learning abilities of adult females affected by the Rett syndrome. The gene and its effect on early development, therefore, is revealed to play a key role in the development of adult plasticity, as Krishnan and his team have revealed.

Through a trial and error process and the use of various genetic and pharmacological processes, Krishnan’s team was able to alter the auditory cortex networks sufficiently to help affected female mice learn to retrieve their pups. According to the team, this shows the mice were able to detect the pups’ squeals correctly, something that was previously impossible for female mice affected by the syndrome.

There is still significant work to be done in identifying the way different individuals respond to MECP2 mutation. The reason why females are mainly the ones affected by the syndrome is that they have two X chromosomes. This means that only one is affected by MECP2 mutations, while in the case of males, the impairment of their single X chromosome usually leads to fatal consequences.

However, since females are affected randomly and there is no way to pinpoint which cells are affected by the “bad batch” MECP2 gene, a wide range of unwanted effects can result in all individuals suffering from the Rett syndrome, and finding treatments for all cases can prove to be challenging in the long run.