Hippocampal CA1 pyramidal neurons show impaired dendritic spine density and morphology only in presymptomatic Mecp2 mutant mice

C. A. CHAPLEAU, G. CALFA, L. POZZO-MILLER

Congreso; Society for Neuroscience-41st Annual Meeting; 2011

Alterations in dendritic spine density and morphology have been consistently documented in numerous disorders associated with intellectual disabilities, such as Rett syndrome (RTT). RTT is an X chromosome-linked disorder that affects approximately 1:15,000 females worldwide and is the leading cause of severe intellectual disabilities in females. Mutations in MECP2, the gene encoding methyl-CpG-binding protein-2, have been identified in ~90% of RTT individuals. Previous work in our laboratory using postmortem brain tissue from female RTT individuals demonstrated that hippocampal CA1 pyramidal neurons have lower dendritic spine density than age-matched unaffected female individuals (Chapleau et al. Neurobiol Dis 2009). Furthermore, previous studies in presymptomatic Mecp2-deficient mice (~P20) or the cell-autonomous expression of mutant MECP2 in postmitotic CNS neurons maintained in slice culture from neonatal rats revealed lower dendritic spine density in several brain regions, including hippocampal CA1 pyramidal neurons. To understand the role of MeCP2 on dendritic spine formation/maintenance, we analyzed dendritic spine density by quantitative confocal microscopy in mice that express a truncated non-functional MeCP2 protein (Jaenisch strain). Dendritic spine density in CA1 pyramidal neurons of symptomatic Mecp2 mutant mice (P40-60) was not statistically different than that in age-matched wildtype littermates (wildtype: 14.41±1.38 spines per 10μm of dendritic length vs. Mecp2 mutant: 16.58±1.18 spines/10μm; n=5 mice; p=0.266). Organotypic slice cultures from P7-9 mice were used to evaluate dendritic spines earlier during development. Consistent with earlier reports from presymptomatic P14 Mecp2 null mice (Bird strain; Chao et al. Neuron 2007), CA1 pyramidal neurons in slice cultures from P7-9 presymptomatic Mecp2 mutant mice had lower dendritic spine density than those from wildtype slice cultures (wildtype: 8.05±0.67 spines/10μm n=5 mice vs. Mecp2 mutant: 5.31±0.98 spines/10μm; n=4 mice; p=0.04). These data demonstrate that proper MeCP2 function is required for the early development of dendritic spines in CA1 pyramidal neurons, and that a secondary compensatory mechanism (homeostatic plasticity?) allows reaching comparable spine density in symptomatic Mecp2 mutant mice and their wildtype littermates. Thus, the use of a “dendritic spine phenotype” as an endpoint for the evaluation of potential treatments in Mecp2 deficient mice should be restricted to presymptomatic animals, with therapeutic interventions starting as early as possible during postnatal development.