Central Nervous System Development

Neuronal Production and Migration

The expansion of the cortex occurs through two processes that take place in parallel: a lateral expansion process that allows the surface of the cortex to grow, and a radial expansion process that leads to an increase in its thickness. The total number of neurons in a mature human brain is estimated at between 3 and 100 billion. The cortex is initially generated from a radially oriented monolayer of proliferative neuroepithelial cells lining the walls of the lateral ventricles—the ventricular zone (VZ). Around the seventh gestational week in humans a second proliferative zone, the inner subventricular zone (SVZ), appears, derived from precursors in the VZ. The cells of the inner SVZ do not adopt a radial conformation. More recently, a third proliferative zone has been identified in the developing neocortex: the outer SVZ, which appears in humans around gestational week 11. In humans, this outer SVZ displays prolonged proliferation. This difference in the behavior of neuronal precursors has been hypothesized to explain the impressive evolutionary expansion and folding observed in the surface of the neocortex.

These proliferative zones, situated on the dorsal side of the lateral ventricles, give rise to the excitatory (glutamatergic) neurons of the different cortical layers (the cortex in mammals consists of six layers), as well as potentially (as this is still controversial and seems to be species/cell subtype-dependent) a portion of inhibitory neurons (GABAergic interneurons). The other inhibitory neurons derive from another proliferative structure located on the lateral wall of the lateral ventricles, the ganglionic eminence (which is also the source of thalamic neurons) and one located in the preoptic area. Migrating neurons can adopt a radial trajectory by migrating in contact with specialized glial cells, the radial glia, which serve to guide them.

After exiting the mitotic cycle, neurons migrate from the proliferative zones toward the future cortex. The first wave of migratory neurons forms the primitive cortical plate or preplate ( Fig. 52.2 ). The second wave of migratory neurons then splits this primitive plate into two, around gestational week 7, giving rise to a three-layered structure: layer I, which contains the Cajal-Retzius neurons, is located just below the meninges, layer VI, which contains neurons that have already completed their migration, and finally the subplate—a transient structure located below the future neocortex. Consecutive waves of migratory neurons subsequently cross the subplate and the cortical layers already in place, but stop below layer I, thus successively forming layers V, VI, III, and II along what is known as an “inside-out” gradient. Until recently, it was thought that the migration of neurons to the neocortex was complete by around gestational week 24. However, recent studies suggest that GABAergic interneurons continue to be added to the neocortex practically until term. In animal models of encephalopathy of prematurity and in human post mortem tissues of preterm neonates, a rarefaction of some subclasses of cortical interneurons has been demonstrated.

Several molecules involved in controlling neuronal migration and their navigation to the appropriate destinations have been identified. These molecules can be schematically divided into four categories.

• 1.

  Cytoskeletal molecules, which play an important role in the initiation and progression of neuronal movement (extension of the apical process and nucleokinesis). Molecules controlling initiation include Filamin-A (an actin-binding protein that is implicated in periventricular nodular heterotopias) and Arfgef2 (a molecule that plays a role in vesicular trafficking and is involved in periventricular nodular heterotopias associated with microcephaly). Among the molecules controlling progression are Doublecortin (a microtubule-associated protein—MAP—implicated in double cortex syndrome), Lis1 (a MAP implicated in type 1 lissencephaly and Miller Dieker syndrome) and Alpha-1 Tubulin (involved in the formation of tubulin heterodimers).

• 2.

  Signaling molecules that play a role in lamination, such as Reelin (a glycoprotein implicated in a human disorder combining lissencephaly with cerebellar hypoplasia).

• 3.

  Molecules modulating glycosylation that provide a stop signal to migrating neurons, such as POMPT1 (protein O -mannosyltransferase, associated with Walker-Warburg syndrome), POMGnT1 (protein O -mannose beta-1,2-N-acetylglucosaminyltransferase, implicated in muscle-eye-brain disease), and Fukutin (a glycosyltransferase implicated in Fukuyama congenital muscular dystrophy). These three human disorders display type 2 lissencephaly.

• 4.

  In addition to these three principal groups of molecules, neuronal migration can be modulated by other factors such as certain neurotransmitters (glutamate and GABA), molecules derived from peroxisomal metabolism, and certain environmental factors (inflammation, ethanol, and cocaine).

Programmed Neuronal Death

Depending on the brain region under consideration, 15% to 50% of the neurons initially produced die through a physiological process termed programmed cell death or apoptosis. Approximately 70% of the neurons that disappear seem to die between gestational weeks 28 and 41 in humans.

Programmed cell death is a complex mechanism governed by a balance between cell death- and survival-inducing signals, genetic programs involved in cell death or survival, effectors of cell death, and inhibitors of these effectors. Cells that have initiated programmed cell death eventually go onto to be phagocytosed by neighboring glial cells (microglia) without inducing inflammatory phenomena or scar formation. This process is facilitated by changes in the composition of the apoptotic cell membrane (“eat me signals”) which are sensed by the microglia which occurs very early in the apoptotic process. Within the cell death process, the activation of caspases (proteolytic enzymes) in the form of a cascade is a key stage that culminates in DNA fragmentation and the death of the neuron. In addition, it is reported that direct interaction between healthy neurons and microglia can initiate cell death programs or even engulfment of the live cell, which is then “digested” by the microglia in a process called phagoptosis.

Electrical activity appears to be a critical factor for neuronal survival. During the peak period of brain growth in rodents, the administration of substances that block electrical activity induces a serious aggravation of developmental neuronal death in various brain regions. These substances include NMDA receptor inhibitors (MK-801 or ketamine), GABA-A receptor agonists such as antiepileptics (phenytoin, phenobarbital, diazepam, clonazepam, vigabatrin, and valproic acid), and anesthetics (a combination of midazolam, nitric oxide, and isoflurane).

Organization of the Central Nervous System