Neurogenesis and Cell Migration in the Developing Neocortex

The earliest-born neurons of the cortex itself migrate through the preplate, splitting it into the marginal zone and subplate, thus constituting layer 6 of the cortex. Each successive cortical neuron cohort, generated during the last two thirds of gestation in humans, migrates past earlier-born neighbors to their final positions. Thus there is an “inside-out” gradient of cortical neurogenesis: early born neurons are deepest, and those born last, except for Cajal-Retzius cells, are superficial. These distinctions are accompanied by differences in which cortical neurons send their axons dendritic differentiation and connectivity.

Radial migration and the inside-out neurogenesis gradient together produce cortical projection neurons whose axons extend to other cortical regions or subcortical targets, such as the basal ganglia, pons, and thalamus, and use the excitatory neurotransmitter glutamate. Surprisingly, the other major class of cortical neurons, interneurons that use the inhibitory neurotransmitter gamma amino butyric acid (GABA), are not generated within the cortex. Instead, interneuron progenitors are found in two anterior forebrain domains: the medial and caudal ganglion eminences. These progenitors yield postmitotic GABAergic neuroblasts within the ganglion eminences that migrate into the neocortex. Initially, this migration is tangential, that is, parallel to the plane of the cortical sheet. When these neurons reach the cortical area where they will differentiate, they migrate radially in much the same way as projection neurons, using radial glial guides.

In the olfactory bulb, projection neurons (mitral cells) are also generated locally, and GABAergic interneurons migrate from the lateral ganglion eminence by a distinct migratory route called the rostral migratory stream. In some mammals, the rostral migratory stream remains in place and guides newly generated neurons from a proliferative zone called the anterior subventricular zone, or SVZ, to the olfactory bulb, perhaps throughout life. The human brain, however, lacks a rostral migratory stream after birth, and it is unlikely that new olfactory interneurons are generated long into postnatal life. In the cerebellum, interneurons (glutamatergic rather than GABAergic) are generated from a proliferative layer immediately beneath the pia, called the external granule cell layer. The postmitotic granule cells then migrate back into the rudimentary cerebellum, past Purkinje cells (cerebellar projection neurons, generated locally) using a glial guide, the Bergmann glia, to facilitate migration. Thus in several brain regions projection neurons and interneurons are generated in distinct proliferative zones, followed by migration that brings these neurons together to form circuits.

The complex history makes the neocortex vulnerable to developmental changes with potential impact on disease. Behavioral disorders, from autism and attention deficit/hyperactivity disorder (ADHD) to bipolar disorder and schizophrenia, may reflect, in part, changes in neurogenesis and migration. Cortical development demands exquisite precision so that neurons are generated at the right times and get to the right places. Small, but significant disruptions could lead eventually to subtle, but significant alterations of cortical circuits and the social, communicative, and cognitive behaviors they subserve. These hypotheses, which unite a spectrum of psychiatric diseases into a continuum of disorders of development of cortical connectivity, remain to be thoroughly tested.

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