Research Awards
Hannah Kinney, M.D.
Harvard Medical School
"Serotonin in the Rett Medulla"
1-Year Award: $50,000
Research Sponsor: Family and Friends of Lauren Stevens
Final Report (November 2004)
Lay Summary
In this study we demonstrate that the level of serotonin transporters in the dorsal motor nucleus of the vagus and the raphé obscurus in the medulla oblongata decreases significantly with age in control cases but not in Rett patients. These regions in the medulla are critical for the unconscious control of normal breathing, heart rate, blood pressure and temperature and are regulated by serotonin, a naturally occurring brain chemical. The serotonin transporter, which is present only on neurons containing serotonin, controls the amount of serotonin available in the brain by the uptake (transport) of free serotonin back into the neuron. A change in the levels of serotonin transporter in the brain is therefore an indication of abnormal levels of serotonin or serotonin neurons. In this regard, we counted the number of serotonin neurons in the medulla oblongata of Rett and control patients, but observed no significant difference. These observations indicate that while there is no change in the number of serotonin neurons, subtle abnormalities in the development of the serotonin system are present in Rett patients.
This study was performed using tissue autoradiography on frozen medullae of 6 Rett and 6 control cases. While still frozen, the medulla from each case was cut into thin slices and collected onto glass microscope slides. The slides were then incubated in a solution containing 125I-RTI-55 a drug that binds to serotonin transporters that is labeled with radioactive iodine (125I). The sections were then removed from the solution rinsed, dried and then placed against photosensitive film for a pre-determined time. The radiation emitted by the 125I label attached to the RTI-55 reacts with the film producing an image of the medulla upon development. Using computer aided quantitation the density of the serotonin transporter binding in individual regions of the medulla in each Rett and control case was then measured from the film. The transporter binding levels for each region were averaged for all Rett and all controls cases and statistically analyzed to determine if binding levels were different in Rett cases compared to controls. Results of the analysis revealed that serotonin transporter binding decreased significantly with age in the medulla oblongata in control cases but not in Rett patients.
Rett syndrome is a disorder of brain development characterized by gradual cognitive decline following normal development through the first 6-18 postnatal months and is one of the most common causes of mental retardation in females. In addition, Rett patients demonstrate breathing difficulties, abnormal heart rate variability and sudden death. The observations in this study suggest that abnormal levels of serotonin transporter may be responsible for the problems with breathing and heart rate, and incidence of sudden death, associated with Rett. In addition, serotonin plays an important role in the normal development of the brain. Changes in serotonin levels may therefore also be responsible, at least in part, for abnormal brain development in Rett.
Hannah Kinney, M.D.Harvard Medical School
"Serotonin in the Rett Medulla"
1-Year Award: $50,000
Research Sponsor: Family and Friends of Lauren Stevens
Final Report (November 2004)
Lay Summary
In this study we demonstrate that the level of serotonin transporters in the dorsal motor nucleus of the vagus and the raphé obscurus in the medulla oblongata decreases significantly with age in control cases but not in Rett patients. These regions in the medulla are critical for the unconscious control of normal breathing, heart rate, blood pressure and temperature and are regulated by serotonin, a naturally occurring brain chemical. The serotonin transporter, which is present only on neurons containing serotonin, controls the amount of serotonin available in the brain by the uptake (transport) of free serotonin back into the neuron. A change in the levels of serotonin transporter in the brain is therefore an indication of abnormal levels of serotonin or serotonin neurons. In this regard, we counted the number of serotonin neurons in the medulla oblongata of Rett and control patients, but observed no significant difference. These observations indicate that while there is no change in the number of serotonin neurons, subtle abnormalities in the development of the serotonin system are present in Rett patients.
This study was performed using tissue autoradiography on frozen medullae of 6 Rett and 6 control cases. While still frozen, the medulla from each case was cut into thin slices and collected onto glass microscope slides. The slides were then incubated in a solution containing 125I-RTI-55 a drug that binds to serotonin transporters that is labeled with radioactive iodine (125I). The sections were then removed from the solution rinsed, dried and then placed against photosensitive film for a pre-determined time. The radiation emitted by the 125I label attached to the RTI-55 reacts with the film producing an image of the medulla upon development. Using computer aided quantitation the density of the serotonin transporter binding in individual regions of the medulla in each Rett and control case was then measured from the film. The transporter binding levels for each region were averaged for all Rett and all controls cases and statistically analyzed to determine if binding levels were different in Rett cases compared to controls. Results of the analysis revealed that serotonin transporter binding decreased significantly with age in the medulla oblongata in control cases but not in Rett patients.
Rett syndrome is a disorder of brain development characterized by gradual cognitive decline following normal development through the first 6-18 postnatal months and is one of the most common causes of mental retardation in females. In addition, Rett patients demonstrate breathing difficulties, abnormal heart rate variability and sudden death. The observations in this study suggest that abnormal levels of serotonin transporter may be responsible for the problems with breathing and heart rate, and incidence of sudden death, associated with Rett. In addition, serotonin plays an important role in the normal development of the brain. Changes in serotonin levels may therefore also be responsible, at least in part, for abnormal brain development in Rett.