Hippocampal Pyramidal Neurons Switch from a Multipolar Migration Mode to a Novel “Climbing” Migration Mode during Development

Abstract

The hippocampus plays important roles in brain functions. Despite the importance of hippocampal functions, recent analyses of neuronal migration have mainly been performed on the cerebral neocortex, and the cellular mechanisms responsible for the formation of the hippocampus are not yet completely understood. Moreover, why a prolonged time is required for hippocampal neurons to complete their migration has been unexplainable for several decades. We analyzed the migratory profile of neurons in the developing mouse hippocampal CA1 region and found that the hippocampal pyramidal neurons generated near the ventricle became postmitotic multipolar cells and accumulated in the multipolar cell accumulation zone (MAZ) in the late stage of development. The hippocampal neurons passed through the pyramidal layer by a unique mode of migration. Their leading processes were highly branched and made contact with many radial fibers. Time-lapse imaging revealed that the migrating cells changed their scaffolds from the original radial fibers to other radial fibers, and as a result they proceed in a zigzag manner, with long intervals. The migrating cells in the hippocampus reminded us of "rock climbers" that instead of using their hands to pull up their bodies were using their leading processes to pull up their cell bodies. Because this mode of migration had never been described, we called it the "climbing" mode. The change from the "climbing" mode in the hippocampus to the "locomotion" mode in the neocortex may have contributed to the brain expansion during evolution.

PDK1–Akt pathway regulates radial neuronal migration and microtubules in the developing mouse neocortex

“…1G and Movies S1 and S2). The average speed of locomotion of control GFP + cells was 21.1 ± 4.5 μm/h (mean ± SD), consistent with previous findings (26). However, mutant neurons migrated at the significantly reduced speed of 14.5 ± 3.9 μm/h (Fig.…”

“…Neocortical neurons move discontinuously and change their speed relatively frequently (26,40), suggesting that they may be equipped with mechanisms that allow them to adjust their radial migration in response to changes in the extracellular environment. In this regard, growth factor stimulation triggers transient Akt activation, which decays within 10-30 min depending on the stimulus and cell type (16,41).…”

Distinct Lineage-Dependent Structural and Functional Organization of the Hippocampus

“…Nonetheless, our data suggest that this special morphological change likely facilitates the sequential deposition of the neuronal progeny of individual RGPs along the stratum pyramidale and the formation of a predominantly one-layered hippocampus. A new mode of neuronal migration in the hippocampus has recently been reported (Kitazawa et al, 2014) and may also contribute to the horizontal organization of hippocampal pyramidal neurons.…”

CA1 pyramidal cell diversity enabling parallel information processing in the hippocampus

“…Hippocampal laminar formation takes places in an inside-out pattern, in which earlier-born cells form the deeper part of the PC layer, whereas the later-born neurons pass the older cells and settle in the more superficial part, as in the neocortex 138–140 . However, in contrast to the relatively straight path of the radially migrating neocortical neurons, hippocampal cells migrate toward the hippocampal plate obliquely at first, followed by a more conventional radial route 141 . In addition, neocortical migrating neurons typically proceed using a single radial fiber as scaffold, whereas migrating future hippocampal pyramidal neurons use multiple radial glial fibers and migrate considerably more slowly 137 .…”