Reference:
ANRn.a.6-NEURn.a.003
Abstract:
PROJECT SUMMARY – Scientific Background and Objectives�Mutations in the gene encoding the protein MeCP2, a transcriptional regulator binding methylated DNA, are causing neurological disorders – including Rett syndrome (RTT) – characterized by an apparently brain development normal.�The mice with truncated versions of MeCP2 show similar neurological deficits in patients RTT.�Deficits in dendritic morphology as well as ?a possible link between MeCP2 and BDNF pathway have been reported, but the pathophysiology of RTT, and the consequences on neuronal and synaptic function ?s inactivation of MeCP2 remains unknown.�We therefore propose a comprehensive electrophysiological study of synaptic function and changes of expression tied to ??absence of MeCP2 to contribute to the emergence of ??synaptic hypothesis of RTT based on possible alterations in the ability of synapses MeCP2-deficient cells to produce forms of synaptic plasticity related activit�RESUME PROJECT – Description�. oReview We propose and identify synaptic deficits in the MeCP2-deficient mice and the “synaptic” genes regulated by MeCP2�* Mice MeCP2- deficient exhibit deficits ?learning related to the hippocampus and the amygdala ?.The first objective (Eq.1, Strasbourg: 1-18 months) is to characterize deficits pre-and postsynaptic mice with.�Patch clamp recordings will be made ??in brain slices containing the lateral amygdala and the hippocampus from heterozygous female wild-type genotype (WT) or mutated (Xmecp2308 / X).The presence or absence of MeCP2 be determined in the recorded neurons.�As in humans and mouse neuronal function and / or synaptic seems normal and deteriorates over time, the recordings will be made ??at different postnatal ages (hemizygous males Xmecp2308 / homozygous females (Xmecp2308 / Xmecp2308).�* The third objective (Eq.1 and Eq.2 Cochin, 1-36 months) aims to identify candidate genes whose l ?term related neuronal synaptic physiology depends MeCP2. corr�lerons We expression changes of selected (single cell RT-PCR) for synaptic alterations genes. ?As identifying genes regulated by MeCP2 is necessary for the understanding of bases of synaptic and neuronal dysfunction, we will undertake a differential transcriptome analysis in the lateral amygdala ?d ?WT animals or MeCP2-deficient, or not subject to a condition by peur.RESUME PROJECT – Results Expected�Key findings arising directly from the project are�1) ?identification deficits pre-and / or post-synaptic related to impairment of MeCP2�2) In relation to the synaptic alterations, the identification of ??candidates whose expression is associated with MeCP2 gene�3) Beyond three years of the program, ?identification of these correlated with deficits observed genes expected to try compensatory strategies Cellular�One originality of the project comes from the use of ?mosaic created by the cell ?X inactivation to determine extrinsic and intrinsic factors leading to neuronal deficits.�It ?s ?s there is a unique opportunity to measure ?importance of these factors in synaptic plasticity.�In addition, thanks to the approach ?differential transcriptome that we will carry in ?amygdala following physiological activation by
PROJECT DETAILS
beginning: 2006.
end: 2009.
Country of research: France
Counry of funding source: France
Funding organization: The French National Research Agency
Financing: NATIONAL FUNDINGS – 360 000 €