Hippocampal CA1 pyramidal neurons of Mecp2 mutant mice show a dendritic spine phenotype only in the presymptomatic stage

Alterations in dendritic spines have been documented in numerous neurodevelopmental disorders associated with intellectual disabilities, including Rett syndrome (RTT). RTT, an X chromosome-linked disorder linked to mutations in MECP2, is the leading cause of severe intellectual disabilities in females. Mecp2-deficient mouse strains have revealed lower dendritic spine density in several brain regions. To understand the role of MeCP2 on excitatory synapse formation and maintenance, we analyzed dendritic spines of CA1 pyramidal neurons in the hippocampus of Mecp2tm1.1Jae male mutant mice by either confocal microscopy or transmission electron microscopy (EM). At postnatal-day 7 (P7) and well before the onset of RTT-like symptoms, hippocampal CA1 pyramidal neurons from Mecp2 mutant mice showed lower dendritic spine density than in those from wildtype littermates. Intriguingly, at P15 (still presymptomatic) or at a later age with established symptoms (P40-60), dendritic spine density did not differ between Mecp2 mutant and wildtype CA1 neurons. Consistently, stereological analyses at the EM level revealed comparable density of asymmetric spine synapses between symptomatic Mecp2 mutant and wildtype littermates. These results raise caution regarding the use of dendritic spine density in hippocampal neurons as a phenotypic endpoint for the evaluation of therapeutic interventions in symptomatic Mecp2-deficient mice, yet raise intriguing questions regarding the role of MeCP2 in later stages of excitatory synapse and dendritic spine maintenance.