MeCP2 Is Critical for Maintaining Mature Neuronal Networks and Global Brain Anatomy during Late Stages of Postnatal Brain Development and in the Mature Adult Brain

Abstract

Mutations in the X-linked gene, methyl-CpG binding protein 2 (Mecp2), underlie a wide range of neuropsychiatric disorders, most commonly, Rett Syndrome (RTT), a severe autism spectrum disorder that affects about one in 10,000 female live births. Because mutations in the Mecp2 gene occur in the germ cells with onset of neurological symptoms occurring in early childhood, the role of MeCP2 has been ascribed to brain maturation at a specific developmental window. Here, we show similar kinetics of onset and progression of RTT-like symptoms in mice, including lethality, if MeCP2 is removed postnatally during the developmental stage that coincides with RTT onset, or adult stage. For the first time, we show that brains that lose MeCP2 at these two different stages are actively shrinking, resulting in higher than normal neuronal cell density. Furthermore, we show that mature dendritic arbors of pyramidal neurons are severely retracted and dendritic spine density is dramatically reduced. In addition, hippocampal astrocytes have significantly less complex ramified processes. These changes accompany a striking reduction in the levels of several synaptic proteins, including CaMKII α/β, AMPA and NMDA receptors, and the synaptic vesicle proteins Vglut and Synapsin, which represent critical modifiers of synaptic function and dendritic arbor structure. Importantly, the mRNA levels of these synaptic proteins remains unchanged, suggesting that MeCP2 likely regulates these synaptic proteins post-transcriptionally, directly or indirectly. Our data suggest a crucial role for MeCP2 in post-transcriptional regulation of critical synaptic proteins involved in maintaining mature neuronal networks during late stages of postnatal brain development.

Functional recovery with recombinant human IGF1 treatment in a mouse model of Rett Syndrome

“…IGF1 treatment abolishes this plasticity and stabilizes the underlying circuits and synapsespossibly via effects on inhibitory systems in the cortex (51) or on homeostatic mechanisms (52). The effect on functional circuits in the adult visual cortex reflects the emerging consensus that the consequences of MeCP2 loss are felt throughout life (53)(54)(55).…”

Expression of Phospho-MeCP2s in the Developing Rat Brain and Function of Postnatal MeCP2 in Cerebellar Neural Cell Development

“…In addition, considering the delay in the phenotypic onset of RTT caused by germline Mecp2 mutations and the pattern of MeCP2 expression, it is of great value to explore the function of MeCP2 in the postnatal brain. It has been shown that deletion of MeCP2 after birth produces phenotypes comparable to those in Mecp2-null mice and disturbs mature neuronal networks as well as the expression of synaptic proteins [24,25]. These findings indicate the requirement of MeCP2 to maintain brain functions in the postnatal period.…”

Human-specific regulation of MeCP2 levels in fetal brains by microRNA miR-483-5p

“…These findings argue that the levels of MeCP2 must be tightly regulated to ensure normal neurological function. Importantly, it is increasingly clear that maintenance of MeCP2 levels throughout life is critical, as revealed by recent reports demonstrating that inducible adult knockout of Mecp2 recapitulated the germline-null phenotypes (McGraw et al 2011;Cheval et al 2012;Nguyen et al 2012). In human brains, MeCP2 protein level is repressed during the fetal stages and elevated during postnatal development (Balmer et al 2003), which could be critical for the timely regulation of expression of hundreds of downstream genes (Chahrour et al 2008).…”