Learning and memory and synaptic plasticity are impaired in a mouse model of Rett syndrome.
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.
Moretti
Paolo
P
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
Levenson
Jonathan M
JM
Battaglia
Fortunato
F
Atkinson
Richard
R
Teague
Ryan
R
Antalffy
Barbara
B
Armstrong
Dawna
D
Arancio
Ottavio
O
Sweatt
J David
JD
Zoghbi
Huda Y
HY
D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D066298:In Vitro Techniques; D007858:Learning / Q000502:physiology; D008297:Male; D008568:Memory / Q000502:physiology*; D008569:Memory Disorders / Q000235:genetics / Q000503:physiopathology; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009473:Neuronal Plasticity / Q000235:genetics*; D015518:Rett Syndrome / Q000235:genetics* / Q000503:physiopathology*; D009435:Synaptic Transmission / Q000502:physiology*
C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2