Neuronal migration and its disorders affecting the CA3 region

Abstract

In this review, we focus on CA3 neuronal migration disorders in the rodent. We begin by introducing the main steps of hippocampal development, and we summarize characteristic hippocampal malformations in human. We then describe various mouse mutants showing structural hippocampal defects. Notably, genes identified in human cortical neuronal migration disorders consistently give rise to a CA3 phenotype when mutated in the mouse. We successively describe their molecular, physiological and behavioral phenotypes that together contribute to a better understanding of CA3-dependent functions. We finally discuss potential factors underlying the CA3 vulnerability revealed by these mouse mutants and that may also contribute to other human neurological and psychiatric disorders.

Keywords: epilepsy; hippocampus; lamination; mouse mutant; neurodevelopment.

Figure 1

The developing hippocampus. Radial glial cells are represented with their somata in the ventricular zone (VZ) and long basal processes extending up to the marginal zone (MZ). These processes serve as guides for migration. Cajal Retzius cells are schematized in brown. Migration pathways across the intermediate zone (IZ) are indicated by arrows. The hippocampal plate (HP) is shown in white, gray, and black to indicate the CA1, CA2, and CA3 fields respectively. The dentate gyrus (DG) is indicated as a V-shaped structure, at this stage the inferior blade (shown in white) is not completely formed, whereas the superior blade (shown in mottled gray) is taking shape. A BrdU injection at E18 in the rat, with sacrifice 4 days later reveals BrdU-labeled cells as schematized by the black dots: cells born at E18 have already reached the CA1 developing pyramidal cell layer, whereas CA3 cells are still found in the IZ, requiring another full day to cross the CA3 pyramidal cell layer. An inset shows the organization of somata in the pyramidal cell layer. Five successive steps of development are indicated, (1) cell proliferation and neurogenesis in the VZ; (2) a multipolar phase above the VZ; (3) a bipolar phase of migration through the IZ; (4) insertion in the hippocampal plate; (5) settling in the appropriate layer. Schema based on data shown in Altman and Bayer (1990b), Figure 3.

Figure 2

A selection of mouse mutants showing somal lamination defects in the hippocampus. Underlined genes are known to be involved in cortical malformations in human. Frag, Fragmented. Broken lines indicate degrees of fragmentation. Asterisks indicate either heterotopic cells or diffusely packed cells. Schemas based on images presented in the following papers: (Del Río et al., ; Fleck et al., ; Wenzel et al., ; Corbo et al., ; Homma et al., ; Petrone et al., ; Kappeler et al., ; Keays et al., ; Enomoto et al., ; Cheah et al., 2012). Kif2a mutants die at birth, the P0 images shown in Homma et al. (2003) are similar to Dcx-KO brains, we have hence extrapolated these data in our schema depicting adult brains.

Figure 3

Morphological and functional abnormalities in the Dcx-KO hippocampus. Upper images show coronal slices of the adult Dcx-KO hippocampus (right) compared to wild-type (WT, left). Red arrows in the KO image point to the internal (upper) and external (lower) CA3 layers. Whole cell recordings and biocytin fills were performed to characterize internal (int) and external (ext) pyramidal cells. (A) WT cell; (B) KO external cell; (C) KO internal cell (taken and modified from Bazelot et al., Figure 5, published by John Wiley & Sons Ltd). Analyses of cell morphologies revealed reduced lengths of apical dendrites for external layer cells and reduced lengths of basal dendrites for internal layer cells (Bazelot et al., 2012). Red labeling on dendrites schematizes mossy fiber innervation in the form of post-synaptic thorny excrescence-like spines. Note non-continuous innervation on apical dendrites of external layer cells, and basal as well as apical innervation on internal layer cells (schematizing data presented in Bazelot et al., , Figure 4). (D) Whole cell recordings taken from Bazelot et al. (2012) Figure 6 (published by John Wiley & Sons Ltd) revealed that KO cells are more excitable than their WT counterparts. In response to identical depolarizing current injection, KO cells fired at higher frequencies.