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

• Published in: The Journal of neuroscience Vol. 26; no. 1; pp. 319 - 327
• Main Authors: Moretti, Paolo, Levenson, Jonathan M, Battaglia, Fortunato, Atkinson, Richard, Teague, Ryan, Antalffy, Barbara, Armstrong, Dawna, Arancio, Ottavio, Sweatt, J. David, Zoghbi, Huda Y
• Format: Journal Article
• Language: English
• Published: United States Soc Neuroscience 04-01-2006; Society for Neuroscience
• Subjects: Animals; Disease Models, Animal; Female; In Vitro Techniques; Learning - physiology; Male; Memory - physiology; Memory Disorders - genetics; Memory Disorders - physiopathology; Methyl-CpG-Binding Protein 2 - genetics; Methyl-CpG-Binding Protein 2 - physiology; Mice; Mice, Transgenic; Mutation; Neurobiology of Disease; Neuronal Plasticity - genetics; Rett Syndrome - genetics; Rett Syndrome - physiopathology; Synaptic Transmission - physiology
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.2623-05.2006

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 (Mecp2(308)) 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 Mecp2(308) mice. Hippocampus-dependent spatial memory, contextual fear memory, and social memory were significantly impaired in Mecp2(308) mutant males (Mecp2(308/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 Mecp2(308/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 Mecp2(308/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.