The importance of time in the treatment of Rett Syndrome

The research team led by Dr Àngels García-Cazorla (IRSJD) has broken new ground in improving the treatment of Rett Syndrome. Researchers at the Sant Joan de Déu Research Institute (IRSJD) and the Bellvitge Biomedical Research Institute (IDIBELL) have found that early GABAergic modulation may offer a promising strategy for affected children.

Rett syndrome is a severe neurodevelopmental disorder characterised by a regression in neurological development. Patients present symptoms such as autistic traits, respiratory problems, loss of acquired abilities such as speech, nonverbal communication and the use of the hands, and organic dysfunctions.

The disease is caused by a malfunction of the MeCP2 protein, which acts as a gene regulator. This causes alterations at the neuronal level and affects the function of GABA, the major inhibitory neurotransmitter in the brain. This dysfunction has been associated with different symptoms characteristic of Rett syndrome.

Previous studies have shown that restoring GABAergic neurotransmission may partially improve Rett syndrome in mouse models. However, it is also important to explore whether the time frame of the disease is important in the development of symptoms.

"On the one hand, our team wanted to analyse whether there was a direct relationship between the GABAergic synapses and MeCP2 and, on the other hand, study how and when the alterations take place during development," explains Dr Àngels García-Cazorla.

The results of the study show a direct relationship between the MeCP2 protein and the expression of a type of GABA receptors. In cell systems without expression of these GABA receptors, when human MeCP2 protein was transfected, it was possible to detect receptor expression. In contrast, there was no expression when mutated MeCP2 protein was transfected.

The research team also observed that in presymptomatic mice there was reduced expression of parts of the GABA receptor and the KCC2 chloride channel. These results highlight the evolutionary nature of the disease: its molecular base is different depending on when it is identified, including in the period when it has not yet been detected phenotypically.

These results demonstrate the importance of performing an early intervention, at the time of detection of Rett Syndrome, and of developing new drugs that improve the modulation of the GABA receptor for use in the initial clinical stages. When designing therapies it is important to pay attention to the dynamic nature of the disease, because what is effective at one stage of the disease may not be effective at another.

"This study confirms what we suspected: the importance of the time frame when addressing the symptoms of the disease, given that the changes that occur depend on the stage, especially the early presymptomatic stages," explains Dr Àngels García-Cazorla.

Reference article

Oyarzabal A, Xiol C, Castells AA, Grau C, O'Callaghan M, Fernández G, Alcántara S, Pineda M, Armstrong J, Altafaj X, García-Cazorla A. Comprehensive Analysis of GABA A-A1R Developmental Alterations in Rett Syndrome: Setting the Focus for Therapeutic Targets in the Time Frame of the Disease. Int J Mol Sci, 21 (2) 2020 Jan 14