EL PLAN DE DESARROLLO FRENTE A LA EMERGENCIA SANITARIA

2.5.1.1 Neurulation and neurogenesis

The CNS starts to develop at neurulation from cells originating from the ectodermal embryonic layer, taking place already at 3-4 weeks of gestation. At neurulation the neural plate is folded into the neural tube, which will eventually develop into the brain and the spinal cord. In the developing cerebral cortex neuroepithelial cells (NECs) attach to the ventricular surface and the pial lamina with long processes spanning the entire thickness of the cortex. They undergo symmetrical cell divisions to generate enough progenitor cells to account for all the neurons of the neocortex. (Figure 4a) (Jiang and Nardelli, 2016)

In the beginning of neurogenesis, the NECs develop into radial glial cells (RGCs). The RGCs are capable of symmetric cell divisions for the purpose of maintaining the cell pool, but most commonly the RGCs drive neurogenesis forwards through asymmetric cell divisions. In the direct route of neurogenesis, one division produces a new RGC and a neuron, whereas in the indirect route one division produces a new RGC and an intermediate precursor cell (IPC), which usually divides symmetrically into two neurons. Both NECs and RGCs engage in interkinetic nuclear migration (INM) in which the nucleus moves periodically in apical and basal directions along the length of the cell in a series of events that are coordinated with cell divisions. The purpose of the interkinetic movements is not well understood, but nevertheless it is important because the failure of INM disturbs neurogenesis. The inhibitory and excitatory neurons of the cortex are derived from distinct lineages of RGC cells. (Jiang and Nardelli, 2016)

2.5.1.2 Radial neuronal migration

The glutamatergic pyramidal neurons of the cortex are born in the subventricular zone (SVZ) of the pallium and then migrate radially through the intermediate zone (IZ) to the cortical plate. The RGCs provide a scaffold along which the neurons migrate and assemble once they have reached their

destinations. In the lower IZ, the newly born migrating neurons adopt a multipolar morphology for a short period while they explore the environment for extrinsic cues that guide their migration. The next phase of neuronal migration involves a transition to bipolar morphology with a leading process oriented towards the pial surface and a trailing process oriented towards the ventricle. The six-layered laminar organisation of the neocortex is formed by sequential waves of migrating neurons. The cortical layers form from the inside out: the neurons on the most internal layers arrive first and the subsequent waves of migratory neurons travel past them. (Jiang and Nardelli, 2016) (Figure 4)

2.5.1.3 Tangential neuronal migration

Tangential neuronal migration is performed primarily by the GABAergic interneurons of the cerebral cortex. (Marin, 2013) In tangential migration the migrating neurons migrate parallel to the pial surface over long distances. Most GABAergic interneurons are derived from progenitors in the lateral and medial ganglionic eminences (LGE and MGE respectively) of the subpallium. In the first phase of tangential migration, the cells migrate to the pallium. The cells are guided by attracting and repulsive cues and on the way to the pallium they avoid the striatum and the preoptic area. The leading process of the migrating neuron branches in response to external cues, which appears to serve as the mechanism that guides the migration. Once the migrating neurons have crossed the subpallium-pallium boundary, the cells become responsive to repelling cues from the subpallium so they do not return. The second phase of tangential neuronal migration is the intracortical dispersion, which involves the spreading of interneurons into the cerebral cortex along migratory streams through the marginal zone, subventricular zone or the subplate. In the last phase of tangential migration, when the migrating interneurons approach their final destination on the cortex, they switch from tangential to radial migration and subsequently adopt their correct laminar position. (Marin, 2013) (Figure 4b)

2.5.1.4 Post-migratory development of neurons

After the neurons have found their correct position in the cortex they further differentiate into various neuronal subtypes. In order to form neural circuits, the neurons extend axons and dendrites to form synaptic contacts with other neurons. The interneurons usually connect locally within the neocortex while the pyramidal projection neurons may extend their axons to more distal targets. Axonal pathfinding is guided by repulsive or attracting cues that can act over long distances (secreted cues) or short distance (cues on the surface of other cells). The receptors for the guidance cues are usually expressed on the surface of the growth cone of the axon. Receptor activation

can trigger intracellular signalling cascades that induce reorganization of the cytoskeleton and thereby direct movement. (Jiang and Nardelli, 2016)

When the axon reaches the target cell, the growth cone is transformed into the presynaptic terminal and thus synaptogenesis is initiated. The generation of synapses continues actively even after birth. In early childhood, until to roughly 2 years of age, excitatory synapses are overproduced in the cortex by activity-dependent synaptogenesis. The inhibitory synapses are slower to develop. During development, the neural circuits are fine-tuned by eliminated some synapses while enforcing other synapses. The development of the cerebral cortex is not complete until roughly 20-25 years of age, even after which the brain continues to show considerable plasticity in the synapses and neuronal connections. The myelination of axons also contributes to the maturation of the neural circuits. (Jiang and Nardelli, 2016)

Figure 4 Summary of the development of the cerebral cortex. a) The neuroepithelial cells

(NECs) proliferate in the VZ to create the neuronal progenitor pool. The NECs can differentiate into radial glial cells (RGCs) and further into neurons either directly or through intermediate precursor cells (IPCs). The newly born neurons migrate from the subventricular zone (SVZ) to the intermediate zone (IZ) and adopt a multipolar morphology. Next, bipolar neurons migrate radially on the RGC scaffold until they arrive at their correct position in the cortical plate (layers L1 – L6) and undergo neuronal maturation. Figure modified from the article by Guo et al. (Guo et al., 2015) b) The glutamatergic neurons of the cerebral cortex originate in the ventricular zone (VZ) in the pallium and undergo radial migration (red arrows). The GABAergic neurons of the cerebral cortex originate in the medial and lateral ganglionic eminences (MGE and LGE respectively) in the subpallium and undergo tangential migration (blue arrows). Figure modified from a review by Luhmann et al. (Luhmann et al., 2015) MGE LGE VZ

b

a