Rett Syndrome (RTT) is a severe neurological disorder diagnosed almost exclusively in girls. Children with RTT appear to develop normally until 6 to 18 months of age, when they enter a period of regression, losing speech and motor skills. Most develop repetitive hand movements, seizures and extreme motor control problems. Irregular breathing patterns characterized by intermittent breath holding, hyperventilation and air swallowing are a particularly devastating symptom of the disorder. In some cases the irregular breathing can lead to death due to sudden respiratory arrhythmia. It is worthwhile to note that individuals with drastic respiratory alterations can spontaneously display transient periods of normal breathing and that breathing can normalize during sleep. RTT leaves its victims profoundly disabled, requiring maximum assistance with every aspect of daily living. There is no cure.
At birth, the mouse model of RTT exhibits typical breathing and normal content of norepinephrine in the medulla. The medulla is a section of the brainstem that is responsible for autonomic function (all the processes in the body that we take for granted like breathing, digestion, cardiac function, temperature control). Between one and two months of age, the mice displayed breathing disturbances that worsened until fatal respiratory arrest at about two months of age. The breathing disturbances were highly variable from mouse to mouse, as is also the case in individuals with RTT.
This study sheds new light into the mysterious mechanisms that underlie the worsening of neurological symptoms that is so characteristic of RTT. The authors demonstrate that disturbances were detectable in the autonomic control regions of the medulla early on and at a time when mice still exhibited normal breathing. However, as levels of norepinephrine increasingly lessened, breathing disturbances became more evident. A disturbance in one neuromodulator (norepinephrine) typically triggers a cascade of disturbances in other modulatory systems, which include serotonergic pathways. Here the authors show that further degeneration of breathing patterns is associated with a reduction in medullary serotonin content, evident in the mouse at about two months of age.
"Re-focusing on a disturbed neuromodulatory state which was first reported in the late 1980's by Huda Zoghbi, is very good news, as disturbances in neuromodulation are potentially easy to control pharmacologically. Based on our findings, there are two obvious next steps: 1) Develop pharmacological ways to compensate for the disturbances in the modulatory milieu first in mutant mice and then in patients. This strategy holds great promise to help individuals with RTT in the near future. 2) Investigate the cellular basis that leads to the decrease in norepinephrine and subsequent serotonin content, which in the long-term could contribute toward the development of a cure for RTT." stated Jan-Marino Ramirez.
The investigators used a fascinating in vitro approach called the "brainstem slice technique", which enabled them to isolate a still functional and spontaneously active network that in the intact animal controls breathing. Using this isolated neuronal network the scientists were able to unambiguously demonstrate that the "central controller" of breathing is disturbed in the RTT mouse model. The investigators were subsequently able to normalize the breathing rhythm by applying norepinephrine
"Ongoing experiments are now aimed at testing different pharmacological tools in vivo, in order to specifically stimulate the norepinephrine-producing neurons still present in the medulla of the RTT mice. Preliminary data are very encouraging. The Villard lab currently plans to follow up on pharmacological interventions both in mice and in humans in collaboration with clinicians from the Children's Hospital in Marseille," said Jean-Christophe Roux, the RSRF fellow and co-first author of the paper.
"I am gratified that RSRF was able to provide funding for this important research and I am encouraged that it will lead to much needed treatments for children and adults struggling with extreme breathing issues", said Monica Coenraads, co-founder and Director of Research for RSRF.
Since its inception in late 1999, RSRF has become the largest private source of funds for RTT research in the world. For more information on RTT or the Foundation please visit our website at www.rsrf.org