Molecular mechanisms: Angelman region affects serotonin
Mice that model Angelman syndrome or have a duplication of the 15q11-13 chromosomal region have aberrant brain levels of the chemical messenger serotonin, according to a study published 16 August in PLoS One1.
Changes to serotonin and other chemical messengers may account for some of the behavioral symptoms that resemble autism in these mice, the researchers say.
Angelman syndrome is characterized by developmental delay, a happy disposition and seizures. It is caused by a deletion of the maternal copy of the 15q11-13 chromosomal region, or by inactivation of the maternal copy of UBE3A, a gene within this region.
UBE3A is imprinted, meaning that only one copy of the gene, in this case the version inherited from the mother, is active. Duplication of the maternal copy of 15q11-13 leads to symptoms that resemble autism.
Last year, a study in fruit flies showed that UBE3A regulates the production of a family of chemical messengers called monoamines, including serotonin and dopamine2. Both neurotransmitters have been linked to autism.
Some individuals with autism have higher levels of serotonin in their blood and lower activity of a serotonin transporter than controls do. These findings suggest that drugs that balance serotonin levels, such as certain antidepressants, could treat symptoms of autism. Results of clinical trials with antidepressants have been disappointing so far, however.
In the new study, researchers looked at levels of monoamines in the brains of several sets of mice: those lacking either the maternal or paternal version of UBE3A, and those with maternal or paternal duplications of the full region.
Mice lacking the maternal copy of UBE3A, but not those missing the paternal copy, have elevated brain levels of serotonin, the study found. Conversely, mice with a duplication of the paternal copy have less brain serotonin than do controls.
The latter result suggests that UBE3A is not sufficient for alterations in serotonin levels, as the paternal copy of UBE3A is not expressed. The results are in line with behavioral studies, as only mice with the paternal 15q duplication show autism-like behaviors.
Dopamine levels are elevated in all the mice, regardless of the source of the mutation.
1: Farook M.F. et al. PLoS One 7, e43030 (2012) PubMed
2: Ferdousy F. et al. Neurobiol. Dis. 41, 669-677 (2011) PubMed