How Do Electric Fields Coordinate Neuronal Migration and Maturation in the Developing Cortex?

Abstract

During development the vast majority of cells that will later compose the mature cerebral cortex undergo extensive migration to reach their final position. In addition to intrinsically distinct migratory behaviors, cells encounter and respond to vastly different microenvironments. These range from axonal tracts to cell-dense matrices, electrically active regions and extracellular matrix components, which may all change overtime. Furthermore, migrating neurons themselves not only adapt to their microenvironment but also modify the local niche through cell-cell contacts, secreted factors and ions. In the radial dimension, the developing cortex is roughly divided into dense progenitor and cortical plate territories, and a less crowded intermediate zone. The cortical plate is bordered by the subplate and the marginal zone, which are populated by neurons with high electrical activity and characterized by sophisticated neuritic ramifications. Neuronal migration is influenced by these boundaries resulting in dramatic changes in migratory behaviors as well as morphology and electrical activity. Modifications in the levels of any of these parameters can lead to alterations and even arrest of migration. Recent work indicates that morphology and electrical activity of migrating neuron are interconnected and the aim of this review is to explore the extent of this connection. We will discuss on one hand how the response of migrating neurons is altered upon modification of their intrinsic electrical properties and whether, on the other hand, the electrical properties of the cellular environment can modify the morphology and electrical activity of migrating cortical neurons.

Keywords: cerebral cortex; dendritogenesis; development; electric field; neuronal migration.

FIGURE 1

Schematic representation of the embryonic mouse cortex and its electrical zones. Two electrically active borders, the subplate (SP) and the marginal zone (MZ), organize neuronal migration in the developing cerebral cortex. The MZ and SP coincide with morphology and migration mode transformations of radially migrating neurons and represent pathways for tangentially migrating neuronal populations: Cajal-Retzius cells and Interneurons. Note the presence of early functional synaptic contacts in the SP and MZ. Axonogenesis and polarization of migrating neurons occur under the SP and dendritogenesis in the MZ. Neuritogenesis is thus enhanced within the two zones. Radial migration is depicted starting from bipolar neurons (BP) in the intermediate zone (IZ) onwards that represent steps mostly studied in terms of electrical activity. RG, radial glia; MP, multipolar neuron; BP, bipolar neuron; MP-BP, transitional morphology of the neuron going through the SP; TT, neuron undergoing terminal translocation; VZ, ventricular progenitors zone; IZ, intermediate zone; CP, cortical plate.

FIGURE 2

Distribution of neurotransmitters and their receptors during cortical development. Enrichment gradients of ion channels and their specific subunits as neurons develop correlate with Ca²⁺ responses to corresponding agonists (graph to the left, adapted from Mayer et al., 2019) and dendritogenesis in the post-migratory neurons. NMDA NR1 subunits clustering in radial glia fibers regulate neuronal layer positioning; NMDA NR2A and B expression switches as progenitors differentiate into neurons. Metabotropic glutamate receptors gradients are representative for mGluRs1, 3, 4, 5, and 8; for AMPARs – GluR1, 2, 3, 4. GABA_A, GABA_B, and GABA_C receptors functional switches in radially migrating neurons are shown. MZ, marginal zone; CP, cortical plate; SP, subplate; IZ, intermediate zone; VZ, ventricular progenitors zone. Major references Hurni et al. (2017), Mayer et al. (2019), and Pasquet et al. (2019).