The role of microtubule-associated protein Kif2a in hippocampal development

The hippocampus is an important structure involved in various sensory, emotional and cognitive processes as part of the limbic circuit, with a critical role particularly in the short- and long-term memory formation and it is functionally associated with spatial learning. The neurons of the hippocampus are organized in three different layers which development is temporally and spatially regulated by gene expression. The mature hippocampal formation will be able to achieve its roles by a complex but orderly connectivity between its different mature fields and with other neocortical association region, subcortical nuclei, medial temporal lobe and parahippocampal areas. In cerebral cortex and hippocampus, alterations in neural proliferation, migration, differentiation and connectivity, often lead to malformations of cortical development (MCD). MCD includes different neurological pathologies such as lissencephaly, microcephaly, polymicrogyria and partial agenesis of the corpus callosum. Most of the genes associated with MCD regulate cytoskeletal dynamics. In this study we sought to analyse the role of the kinesin protein Kif2a, a member of the Kinesin-13 family proteins implicated in microtubule depolymerization. Kif2a mutations have been identified in patients with MCD, suffering epilepsy, microcephaly and intellectual disabilities. Kif2a is involved in neuronal migration having a critical role in the organization and dynamics of the microtubule cytoskeleton. However, the role of Kif2a in cortical development is not completely asset since the Kif2a knock out (KO) mice die right after birth due of feeding issues. In order to study the role of Kif2a in hippocampal formation we use a conditional KO mouse line where Kif2a is deleted from all the glutamatergic neurons of the hippocampus and cerebral cortex. We have analysed the hippocampal formation at post-natal stage P21, when the maturation of the mice hippocampus is completed. The characterization of immunolabelled hippocampal sections of control and mutant mice has been evaluated by confocal microscopy. As expected, the morphology of mutant hippocampal formation appears highly affected compared with the control group. Pyramidal neurons and granular cells in the mutated hippocampus are distributed aberrantly along the hippocampal layers, indicating a defect in radial migration. In addition, the connections between the dentate gyrus (DG) and CA3 is also affected in mutant mice suggesting a role of Kif2a in axon development. Kif2a also has a role in the formation of radial glia of the DG. The disposition of glial intermediate filaments all along the fascia dentata of dentate gyrus, in mutant mice appear completely lost. Finally, we examined the two main population of inhibitory interneurons which determine the fine regulation of the neuronal circuits. We found a differential neuronal distribution in mutant hippocampal sections compared with the control ones which appear similar to the neuronal distribution in the different regions. This may suggest a possible adaptation of interneuron position to maintain inhibitory capacity versus the innervated pyramidal cells. Taking these results together we showed the key role of Kif2a in neuronal migration, connectivity and neuronal circuity regulation in the hippocampus and this possible relation with epileptic susceptibility found in humans carrying Kif2a mutations.