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The Journal of Neuroscience, January 4, 2006, 26(1):319-327; doi:10.1523/JNEUROSCI.2623-05.2006

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Neurobiology of Disease
Learning and Memory and Synaptic Plasticity Are Impaired in a Mouse Model of Rett Syndrome

Paolo Moretti,1,2 Jonathan M. Levenson,3 Fortunato Battaglia,7 Richard Atkinson,1 Ryan Teague,1 Barbara Antalffy,4 Dawna Armstrong,4 Ottavio Arancio,7 J. David Sweatt,3 and Huda Y. Zoghbi1,2,3,5,6

Departments of 1Molecular and Human Genetics, 2Neurology, 3Neuroscience, 4Pathology, and 5Pediatrics, and 6Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas 77030, and 7Center for Dementia Research, Nathan S. Kline Institute for Psychiatric Research–New York University, Orangeburg, New York 10962

Loss-of-function mutations or abnormal expression of the X-linked gene encoding methyl CpG binding protein 2 (MeCP2) cause a spectrum of postnatal neurodevelopmental disorders including Rett syndrome (RTT), nonsyndromic mental retardation, learning disability, and autism. Mice expressing a truncated allele of Mecp2 (Mecp2308) reproduce the motor and social behavior abnormalities of RTT; however, it is not known whether learning deficits are present in these animals. We investigated learning and memory, neuronal morphology, and synaptic function in Mecp2308 mice. Hippocampus-dependent spatial memory, contextual fear memory, and social memory were significantly impaired in Mecp2308 mutant males (Mecp2308/Y). The morphology of dendritic arborizations, the biochemical composition of synaptosomes and postsynaptic densities, and brain-derived neurotrophic factor expression were not altered in these mice. However, reduced postsynaptic density cross-sectional length was identified in asymmetric synapses of area CA1 of the hippocampus. In the hippocampus of symptomatic Mecp2308/Y mice, Schaffer-collateral synapses exhibited enhanced basal synaptic transmission and decreased paired-pulse facilitation, suggesting that neurotransmitter release was enhanced. Schaffer-collateral long-term potentiation (LTP) was impaired. LTP was also reduced in the motor and sensory regions of the neocortex. Finally, very early symptomatic Mecp2308/Y mice had increased basal synaptic transmission and deficits in the induction of long-term depression. These data demonstrate a requirement for MeCP2 in learning and memory and suggest that functional and ultrastructural synaptic dysfunction is an early event in the pathogenesis of RTT.

Key words: Rett syndrome; neurodevelopmental disorders; autism; synaptic plasticity; LTP; LTD; epigenetics; MeCP2; learning and memory

Received May 5, 2005; revised September 14, 2005; accepted November 10, 2005.




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