Learning and Memory and Synaptic Plasticity are Impaired in a Mouse Model of Rett Syndrome
P.Moretti; J.M.Levenson; F.Battaglia; R.Atkinson; R.Teague; B.Antalffy; D.Armstrong; O.Arancio; D.J.Sweatt; H.Y.Zoghbi.
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), non-syndromic 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 BDNF 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, indicating 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 (LTD). 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
Earlier this year, two groups separately described reduced learning and memory in two different mouse models of RTT. Similar experiments are described in this abstract, but for a different, third model of RTT. Confirming earlier studies, these data demonstrate a requirement for MeCP2 in learning and memory and suggest that functional and synapse dysfunction is an early event in RTT disease progression. RSRF has funded the Zoghbi lab extensively.