Time-variant processing in V1: from microscopic (single cell) to mesoscopic (population) levels.

plate, Cdk5 and p35 (a neuronal-specific activator of Cdk5) are required. Both molecules are present in migrating neurons, and inactivation of either of them produces a phenotype somewhat similar to reeler in that cells are positioned in an outside–in gradient 6,7. However, by contrast to the adult reeler, in Cdk5/p35 mutants there is a relatively normal layer I below the subpial layer 8,9 , suggesting that in this mutant cortical plate cells respond normally to Reelin. An interesting observation is that in the Cdk5 −/− mutant, the subplate remains within the cortical plate during development; that is, early-born cortical plate cells are able to traverse the subplate, but late-born cells become positioned below the subplate, forming an underplate. This does not occur in the p35 −/− mutant, in which all or most cortical plate cells are able to cross the subplate 8. It is possible that late-born cortical plate cells require Cdk5 to cross the subplate, but are activated by a factor other than p35 (perhaps p39) 10. An additional point is that the defect in p35 −/− mutants is more severe in dorsomedial cortex, but lateral and ventrolateral cortices are less affected by the mutation, again suggesting that in the latter regions there might be other factors, in addition to p35, that activate Cdk5. Based on these observations, I proposed an hypothesis suggesting that Cdk5 was a key factor in the evolutionary origin of the isocortical inside-out gradient 5. This hypothesis postulated that in the cortical plate of the Cdk5/p35 mutant, and perhaps in that of an ancestral mammal-like reptile with an outside-in pattern of migration, there is, or was, a putative factor that blocks the migration of cells past previously formed cortical-plate cells. Because of the role of Cdk5 in promoting neurite outgrowth and modifying the cytoskeleton 11–13 , and the fact that Cdk5/p35 are expressed in migrating neurons, I suggested that the Cdk5/p35 pathway allows migrating cells to bypass this migratory-suppressing factor. Recently, Cdk5/p35 have been found to be associated with a β-catenin-N-cadherin in the cerebral cortex 14. This study showed that inhibition of Cdk5 kinase activity facilitates in vitro N-cadherin mediated neuronal aggregation. Similary, p35 −/− cells also aggregate to a greater degree compared with wild-type neurons. These findings suggest that, in vivo, Cdk5 avoids the arrest of neuronal migration below older cells by inhibiting N-cadherin-dependent cell aggregation. The Reelin pathway might have participated in the …