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Final Activity and Management Report Summary - INTERMMOODEL (Generation of Interneuron deficient mouse model)

The general objective of INTERMMOODEL was to obtain a definition of the cellular and molecular mechanisms controlling the development of cortical interneurons. To reach this aim, we took a multidisciplinary approach by combining genomic applications, conventional cellular, molecular and electrophysiological methodologies.

To determine the contribution of temporal segregation in the generation of cortical interneuron diversity, we generated transgenic mice lines that allowed to permanently tracing the progeny of distinct interneuronal progenitors. Different mice lines were produced in which the expression of Cre recombinase is restricted to subpallial progenitors of cortical interneurons. For this purpose, we produced BAC transgenes using recombineering technology to insert a Cre recombinase (Cre) under the control of selected transcription factor promoters like Nkx5-1, Nkx6-2 and Pax6.

The three lines contribute with progenitors derivatives to different areas of the mouse brain. Using the Nkx5-1-Cre line we were able to show that the preoptic area (POA), is a novel source of cortical GABA-ergic interneurons in the mouse. Genetic lineage-tracing experiments demonstrated that neurons born in the POA migrate to the neocortex and hippocampus, where they differentiate into a distinct population of GABA-ergic interneurons with relatively uniform neurochemical, morphological and electrophysiological properties. By the Pax6 Cre line we were able to identify how some neurons migrate to integrate into an area of the brain to conform the Globus Pallidus. By means of a Dbx1 Cre line, we were able to identify that the POA were capable of producing a highly diverse population od interneuron that migrates to the cortex.

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