Abstract
Childhood neurodevelopmental disorders like Angelman syndrome and autism may be the result of underlying defects in neuronal plasticity and ongoing problems with synaptic signaling. Some of these defects may be due to abnormal monoamine levels in different regions of the brain. Ube3a, a gene that causes Angelman syndrome (AS) when maternally deleted and is associated with autism when maternally duplicated has recently been shown to regulate monoamine synthesis in the Drosophila brain. Therefore, we examined monoamine levels in striatum, ventral midbrain, frontal cerebral cortex, cerebellar cortex and hippocampus in Ube3a deficient and Ube3a duplication animals. We found that serotonin (5HT), a monoamine affected in autism, was elevated in the striatum and cortex of AS mice. Dopamine levels were almost uniformly elevated compared to control littermates in the striatum, midbrain and frontal cortex regardless of genotype in Ube3a deficient and Ube3a duplication animals. In the duplication 15q autism mouse model, paternal but not maternal duplication animals showed a decrease in 5HT levels when compared to their wild type littermates, in accordance with previously published data. However, maternal duplication animals show no significant changes in 5HT levels throughout the brain. These abnormal monoamine levels could be responsible for many of the behavioral abnormalities observed in both AS and autism, but further investigation is required to determine if any of these changes are purely dependent on Ube3a levels in the brain.
Highlights
Angelman syndrome (AS) is a severe neuro-developmental disorder with a prevalence of approximately 1 in 15,000 individuals
Since our current hypothesis is that Ube3a protein levels alone will have downstream effects on monoamine synthesis, we needed to establish in a quantitative manner if both mouse models used in this study conform to the current imprinting paradigm for Ube3a expression
There is .75% increase in Ube3a protein in the maternal 7p duplication animals but not the paternal duplication animals in the cerebellum and hippocampus (Figure 1). These results are consistent with two previous publications [21,27], making the 7p duplication mouse model a valid model for maternal duplication 15q autism where Ube3a levels are elevated in neurons [30]
Summary
Angelman syndrome (AS) is a severe neuro-developmental disorder with a prevalence of approximately 1 in 15,000 individuals. Characteristic features of this syndrome include developmental delays, speech impairment, ataxia, frequent inappropriate laughter and in some cases abnormal EEG patterns, seizures and microcephaly [1]. Maternal duplications of the 15q11-q13 region are clearly associated with an autism phenotype [6], more broadly classified as Autism Spectrum Disorder (ASD). The major characteristic features of ASD include impairment in social interaction, verbal and non-verbal communication problems, rigid or repetitive behavior and restricted interests [7]. In some studies paternal duplications have been associated with autistic behavior [9]
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