J Neurosci. 2006 Jan 4;26(1):319-27.
Learning and memory and synaptic plasticity are impaired in a mouse model of Rett syndrome
Moretti P, Levenson JM, Battaglia F, Atkinson R, Teague R, Antalffy B, Armstrong D, Arancio O, Sweatt JD, Zoghbi HY.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
Abstract
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.
Lay Summary
Last year, two groups separately described reduced learning and memory in two different mouse models of RTT which lack MeCP2. In this current study, similar experiments are described, but for the third model of RTT, where the normal MeCP2 gene is replaced with a truncated MeCP2 gene. Not surprisingly, the results of this study confirm those of the earlier studies. However, a few novel findings should be highlighted. First, in contrast to the results of human pathological studies, the individual nerve cells of severely affected MeCP2-mutant mice did not display reduced branching patterns. Interestingly, when examined at greater magnification, it was noticed that nerve cells of the MeCP2-mutant mice responsible for learning and memory display a slight, yet significant, decrease in the size of region known as the postsynaptic density (PSD). This is interesting, as the PSD is the site of cell-to-cell communication in the brain. Taken together, these data further demonstrate a requirement for normal MeCP2 in learning and memory and synapse structure, and that these slight anatomical differences may play a role in RTT disease progression.