Altered Ultrasonic Vocalization and Impaired Learning and Memory in Angelman Syndrome Mouse Model with a Large Maternal Deletion from Ube3a to Gabrb3
| Autor: | Corinne M. Spencer, Li Zhu, Yong-hui Jiang, Luis Landa, Yanzhen Pan, Arthur L. Beaudet, Isabel Lorenzo, Murray H. Brilliant, Jeffrey L. Noebels, Jong Yoo |
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| Rok vydání: | 2010 |
| Předmět: |
Male
Mutant lcsh:Medicine Mice 0302 clinical medicine Ultrasonics Imprinting (psychology) lcsh:Science Adenosine Triphosphatases Cerebral Cortex Genetics and Genomics/Medical Genetics Genetics Regulation of gene expression 0303 health sciences Multidisciplinary Homozygote Darkness Null allele Genetics and Genomics/Gene Function Female Chromosome Deletion Research Article congenital hereditary and neonatal diseases and abnormalities Ubiquitin-Protein Ligases Mothers Motor Activity Biology 03 medical and health sciences Chromosome 15 Memory Seizures Genetics and Genomics/Epigenetics Angelman syndrome medicine UBE3A Animals Chromosomal Deletion 030304 developmental biology lcsh:R Membrane Transport Proteins Receptors GABA-A medicine.disease Disease Models Animal Gene Expression Regulation Genetics and Genomics/Disease Models Exploratory Behavior lcsh:Q Angelman Syndrome Vocalization Animal 030217 neurology & neurosurgery |
| Zdroj: | PLoS ONE PLoS ONE, Vol 5, Iss 8, p e12278 (2010) |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0012278 |
| Popis: | Angelman syndrome (AS) is a neurobehavioral disorder associated with mental retardation, absence of language development, characteristic electroencephalography (EEG) abnormalities and epilepsy, happy disposition, movement or balance disorders, and autistic behaviors. The molecular defects underlying AS are heterogeneous, including large maternal deletions of chromosome 15q11-q13 (70%), paternal uniparental disomy (UPD) of chromosome 15 (5%), imprinting mutations (rare), and mutations in the E6-AP ubiquitin ligase gene UBE3A (15%). Although patients with UBE3A mutations have a wide spectrum of neurological phenotypes, their features are usually milder than AS patients with deletions of 15q11-q13. Using a chromosomal engineering strategy, we generated mutant mice with a 1.6-Mb chromosomal deletion from Ube3a to Gabrb3, which inactivated the Ube3a and Gabrb3 genes and deleted the Atp10a gene. Homozygous deletion mutant mice died in the perinatal period due to a cleft palate resulting from the null mutation in Gabrb3 gene. Mice with a maternal deletion (m-/p+) were viable and did not have any obvious developmental defects. Expression analysis of the maternal and paternal deletion mice confirmed that the Ube3a gene is maternally expressed in brain, and showed that the Atp10a and Gabrb3 genes are biallelically expressed in all brain sub-regions studied. Maternal (m-/p+), but not paternal (m+/p-), deletion mice had increased spontaneous seizure activity and abnormal EEG. Extensive behavioral analyses revealed significant impairment in motor function, learning and memory tasks, and anxiety-related measures assayed in the light-dark box in maternal deletion but not paternal deletion mice. Ultrasonic vocalization (USV) recording in newborns revealed that maternal deletion pups emitted significantly more USVs than wild-type littermates. The increased USV in maternal deletion mice suggests abnormal signaling behavior between mothers and pups that may reflect abnormal communication behaviors in human AS patients. Thus, mutant mice with a maternal deletion from Ube3a to Gabrb3 provide an AS mouse model that is molecularly more similar to the contiguous gene deletion form of AS in humans than mice with Ube3a mutation alone. These mice will be valuable for future comparative studies to mice with maternal deficiency of Ube3a alone. |
| Databáze: | OpenAIRE |
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