Mecp2 is required for activity-dependent refinement of olfactory circuits

ALICIA DEGANO; MIN JUNG PARK; JUDY PENATTI; GABRIELE RONNETT

New Orleans, LA, USA

Congreso; 7TH WORLD CONGRESS ON RETT SYNDROME.; 2012

International Rett Science Foundation (IRSF)

Methyl Cytosine Binding Protein 2 (MeCP2) is a structural chromosomal protein that regulates gene expression. Alterations in the levels of Mecp2 have been related to autism spectrum disorders. Studies in mouse models of Mecp2 deficiency have shown that this protein is important for neuronal maturation, neurite complexity, synaptogenesis and synaptic plasticity, although the underlying mechanisms are not completely understood. Our working hypothesis proposes that Mecp2 plays a role in the formation and maturation of neural circuits during development. To test this hypothesis we use the olfactory system as a neurodevelopmental model. This system undergoes postnatal neurogenesis and axons from olfactory neurons form highly stereotyped projections to higher-order neurons, facilitating the detection of possible defects in the course of the establishment of connectivity. We used gene-targeted mice to visualize specific olfactory circuits and in vivo olfactory stimulation paradigms to mimic a condition of ?physiological? synaptic activity. Our present results reveal deficient postnatal refinement of olfactory circuits in Mecp2-null mice after odorant stimulation. This failure in refinement was associated with deficits in the response to odorants, i.e.: activation of Erk1/2 and BDNF production. In addition, we show that olfactory stimulation in wild type animals induced the phosphorylation of Mecp2 in serine 421. Interestingly, the lack of circuitry maturation was prevented by daily treatment with ampakine (CX546, 40 mg/kg), but not valproate (30mg/kg), beginning after the first postnatal week. These observations indicate that increasing synaptic activity at early postnatal age, could circumvent the detrimental effect of the absence of Mecp2 on circuitry maturation. The present results provide evidence for an in vivo role of Mecp2 in activity-dependent maturation of olfactory circuitry and have implications for understanding the mechanism of Mecp2 mutations on neural connectivity.