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mechanisms of GABAergic interneurons axonal branching in developing cerebellum network

Final Report Summary - GABAXONETDEV (mechanisms of GABAergic interneurons axonal branching in developing cerebellum network)

Neuronal diversity relies both on genetic program and local instructive cues. However little is known about how neuron circuit integration timing influence cell-type specific differentiation programs. In cerebellar cortex, molecular layer GABAergic interneuron (MLGI) circuit comprises two subtypes: the Basket and the Stellate cells. They display major morphological differences but present no discriminating genetic marker. It has been proposed that their morphological differences are due to substantially different developmental environments. However, due to persisting lack of evidence to support this view, the question has remained controversial. During this period, we unravel stereotyped migration paths that could elicit the emergence of morphological differences. Our in vivo grafts experiments showed that Basket and Stellate used distinct migratory pathways during neuronal circuit integration. We conducted a series of time-lapse experiments on acute slices and uncovered that a proportion of immature MLGI penetrated the External Granule cell Layer (EGL) where they migrated tangentially during a restricted time period. Using organo-graft experiments, we showed that tangentially migrating MLGI, belong to late integrating stellate cells subpopulation. We showed that the age of progenitors does not influence their migrating capacity; that migration by itself is not sufficient to steer towards a stellate-specific differentiation program when cells differentiated in an immature local environment. Moreover, our data showed that timely controlled environmental changes influence functional maturation within a migrating, genetically homogeneous progenitor cell population. To our knowledge, tangential migration of stellate-cells represents the first indication of an early divergence during basket versus stellate maturation process and put forward the importance of the temporal parameter. We propose here that tangential migration acts as a cell diversity maker by specifically extending the maturation process of Stellate-cells progenitors, thus delaying the onset of differentiation and consequently their local developmental environment maturity.

Studies of cell fate specification, laminar deployment, connectivity, and network dynamics provide a probe to understand circuit pathogenesis in models of neuropsychiatric disorders.