Impact of GDNF family receptor alpha1 for the development of cortical GABAergic interneurons in the mouse brain

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GABAergic inhibitory interneurons form an important part of the cerebral cortex as they synchronize actions of pyramidal cells. The mechanisms controlling inhibitory interneuron diversification and allocation to distinct cortical areas remain poorly understood. The origins of cortical interneurons are the medial and caudal ganglionic eminences (MGE and CGE), as well as the preoptic area (POA), but interneurons characterized by the expression of the calcium-binding protein parvalbumin (PV) are predominantly generated in the MGE. GDNF and its receptor GFRalpha1 have been implicated in the development of GABAergic precursors, but the analysis of their roles in postnatal development is hampered by the lethal phenotype of GFRalpha1 knockout mice due to kidney agenesis. Mouse mutants that lack GFRalpha1 only in cells that are negative for the GFRalpha1 interaction partner RET (cis-only mice), show „PV holes“ in the cortex, i.e. regions without any PV expression that are mostly found in visual and frontal cortex areas. One aim of this study is to prove that GFRalpha1-positive MGE cells in the embryo develop into PV-positive cortical interneurons postnatally. This shall be achieved by genetic fate mapping, as MGE precursors are thought to lose GFRalpha1 expression while migrating to the cortex. In addition, the mechanism which leads to defects in the cis-only mouse will be investigated. Transplantation of embryonic MGE precursors into the early postnatal cis-only cortex will allow distinguishing between a cell-autonomous and a non-cell-autonomous mechanism. Furthermore, analysis of conditional GFRalpha1 knockout mice - with specific GFRalpha1 deletion in GABAergic interneurons - will be performed in order to gain additional insight into the roles of the GFRalpha1 receptor in interneuron development and function.