Analysis of Neuregulin-1 function in the maturatio.. (GABACORT)
Analysis of Neuregulin-1 function in the maturation of cortical GABAergic interneurons: Implications for the etiology of schizophrenia
Start date: May 1, 2008,
End date: Apr 30, 2010
"Schizophrenia is a psychiatric illness affecting nearly 1% of the population that is though to arise as a consequence of abnormal brain development. Structural deficits are relatively subtle in schizophrenia; however, there is evidence for a reduced volume of the neocortex, probably linked to perturbed development of the neuropil, and significant alterations in GABAergic neurotransmission in patients with schizophrenia. Recent genetic studies suggest that Neuregulin-1 (Nrg1) and its receptor ErbB4 are susceptibility genes linked to the disorder. Interestingly, our preliminary observations demonstrate that ErbB4 is specifically expressed by GABAergic interneurons during the postnatal development of the cerebral cortex. The goal of this study is to determine the role of Nrg1/ErbB4 signalling in the maturation of GABAergic interneuron, using interneuron specific ErbB4 mutant mice, in order to get insights into the etiology of schizophrenia. We plan to address the function of Nrg1/ErbB4 using cell culture techniques, in utero manipulations and analyses of interneuron-specific ErbB4 conditional mutants. In brief, we will test whether Nrg1 influences the axonal development of control or ErbB4 mutant cortical interneurons in primary cultures. In addition, we will study the morphological development of individual ErbB4-deficient cortical interneurons in vivo, by in utero electroporation of Cre/GFP plasmids in the place of origin of most cortical interneurons, the medial ganglionic eminence. Furthermore, we will establish the role of Nrg1/ErbB4 in synaptogenesis both in cell cultures and in vivo, scrutinizing the development of GABAergic terminals in control and ErbB4 conditional mutants by confocal analysis, electron microscopy and electrophysiological techniques. Finally, we will address the role of ErbB4 in the regulation of gene expression in the cerebral cortex by comparing the transcriptional profile of the postnatal cortex from WT and ErbB4 conditional mutant"
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