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The human nervous system is the most complex organ system in vertebrates and contains a greater variety of cell types than is found in any other organ. Remarkably, the diversity of cell types that regulate every aspect of our lives is accomplished during a brief span of development encompassing just 3–4 months in humans. It is therefore not surprising that this critical period of gestation is sensitive to interference through environmental factors and pathogens, as well as genetic mutations. For example, extrinsic factors such as alcohol exposure have been shown to decrease neuronal production and, in severe cases, to produce microcephaly and mental retardation (M. W. Miller 1989). In addition, mutations in the doublecortin gene have been shown to dramatically interfere with neocortical development, resulting in epilepsy and in severe cortical malformations such as lissencephaly (des Portes et al. 1998; Gleeson et al. 1998).

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FIGURE 4–15. Key events in the generation of cortical neurons during embryogenesis.Radial glial cells (R, shown in green) undergo interkinetic nuclear migration and divide asymmetrically at the ventricular surface (*) to self-renew and to generate neurons either directly (red cell) or indirectly through the generation of an intermediate progenitor cell (blue). Intermediate progenitor cells subsequently undergo terminal symmetrical division in the subventricular zone (SVZ, ) to generate two neurons. CP = cortical plate; IZ = intermediate zone; SVZ = subventricular zone; VZ = ventricular zone.Source. Reprinted from McAllister AK, Usrey WM, Noctor SC, Rayport S: "Cellular and Molecular Biology of the Neuron," in The American Psychiatric Publishing Textbook of Neuropsychiatry and Clinical Neurosciences, 5th Edition. Washington, DC, American Psychiatric Publishing, 2008, pp. 3–43.

FIGURE 4–16. Migration phases of neocortical neurons during development.During development, neocortical neurons exhibit four distinct phases in migration. Panel A. A time-lapse sequence of a retrovirally labeled neuron expressing the reporter protein green fluorescent protein (GFP) undergoing migration from the proliferative zone to the cortical plate in a cultured brain slice. The sequence begins when the neuron is in the second phase, which consists of migratory arrest for 24 hours or more (shown here at the end of phase two, t = 0 hours), followed by a third phase of retrograde migration toward the ventricle (t = 14–18 hours) and a final phase of polarity reversal and migration toward the cortical plate (CP) (t = 24–96 hours). Before initiating the final phase of radial migration, the neuron develops a leading process oriented toward the CP (white arrowhead). After 96 hours in culture, the migrating neuron had reached its destination at the top of the cortical plate. These neurons often leave a trailing axon in the ventricular zone (VZ, red arrowheads). Panel B. Schematic depicting a neuron (shown in dark green) undergoing the four phases of migration: 1) After being generated by its mother radial glial cell (R, shown in light green), the neuron commences initial radial migration, 2) migratory arrest in the SVZ, 3) retrograde migration, and 4) secondary radial migration. IZ = intermediate zone; SVZ = subventricular zone.Source. Reprinted from McAllister AK, Usrey WM, Noctor SC, Rayport S: "Cellular and Molecular Biology of the Neuron," in The American Psychiatric Publishing Textbook of Neuropsychiatry and Clinical Neurosciences, 5th Edition. Washington, DC, American Psychiatric Publishing, 2008, pp. 3–43.

FIGURE 4–17. Synapse formation of the neuromuscular junction (NMJ).Panel A. Schematic view of the molecular components of a typical NMJ. At a mature NMJ, the presynaptic terminal is separated from the postsynaptic muscle cell by the synaptic cleft. Synaptic vesicles filled with acetylcholine (ACh) are clustered at active zones, where they can fuse with the plasma membrane upon depolarization to release their transmitter into the synaptic cleft. Acetylcholine receptors are found postsynaptically, and glial cells called Schwann cells surround the synaptic terminal. Panel B. Stages in the formation of the NMJ: 1) An isolated growth cone from a motor neuron is guided to the muscle by axon guidance cues. 2) The first contact is an unspecialized physical contact. 3) However, synaptic vesicles rapidly cluster in the axon terminal, acetylcholine receptors start to cluster under the forming synapse, and a basal lamina is deposited in the synaptic cleft. 4) As development proceeds, multiple motor neurons innervate each muscle. 5) Over time, however, all but one of the axons are eliminated through an activity-dependent process, and the remaining terminal matures.Source. Reprinted from Sanes JR, Jessell TM: "The Formation and Regeneration of Synapses," in Principles of Neural Science, 4th Edition. Edited by Kandel ER, Schwartz JH, Jessell TM. New York, McGraw-Hill, 2000, pp. 1087–1114. Copyright 2000, The McGraw-Hill Companies, Inc. Used with permission.

FIGURE 4–18. Neurotrophins and their receptors.Neurotrophins exert their effects through binding to two types of receptors: the low-affinity nerve growth factor receptor (also called p75) and the high-affinity tyrosine kinase receptors (the Trk receptors). Nerve growth factor (NGF) binds primarily to TrkA, and brain-derived neurotrophic factor (BDNF) and neurotrophin 4/5 (NT-4,5) bind primarily to TrkB. The specificity of neurotrophin 3 (NT-3) is less precise; although it mostly binds to TrkC, it can also bind to TrkA and TrkB under some cellular contexts. In addition, all of the neurotrophins bind to p75.Source. Adapted from Jessell TM, Sanes JR: "The Generation and Survival of Nerve Cells," in Principles of Neural Science, 4th Edition. Edited by Kandel ER, Schwartz JH, Jessell TM. New York, McGraw-Hill, 2000, pp. 1041–1062. Copyright 2000, The McGraw-Hill Companies, Inc. Used with permission.

FIGURE 4–19. Ocular dominance columns in visual cortex.Panel A. In the human visual pathway, optic fibers from each eye split at the optic chiasm, half going to each side of the brain. In this schematic drawing, fibers conveying visual information from the left sides of each retina are shown projecting to the left lateral geniculate nucleus (LGN). LGN neurons (in different layers) in turn project to ipsilateral visual cortex (principally to layer 4c). In the geniculate-recipient layers of the mature visual cortex, inputs from the eyes segregate into ocular dominance (OD) columns. Panel B. Radioactive proline injections into one eye of a 2-week-old kitten uniformly label layer 4 in coronal sections of visual cortex, indicating that afferents from that eye are evenly distributed in cortex at this age. However, over the next few weeks, similar injections show a segregation of geniculate afferents into OD columns. Panel C. Schematic diagram of the formation of OD columns within layer 4 of cortex during normal development. Panel D. One eye of a normal monkey was injected with a radioactive tracer that was transported transsynaptically along the visual pathways. Cortical areas receiving inputs from the injected eye are labeled white, revealing an alternating pattern of evenly spaced stripes (section cut tangentially through layer 4c). Panel E. Monocular deprivation alters the development of OD columns. Here the tracer was injected into the nondeprived eye, revealing broader stripes and thus an expansion of the area innervated by the nondeprived eye. Thus, normal experience is a prerequisite to the correct wiring of the cortex.Source. Panel A reprinted from Kandel ER, Jessell T: "Early Experience and the Fine Tuning of Synaptic Connections," in Principles of Neural Science. Edited by Kandel ER, Schwartz JHS, Jessell TM. Stamford, CT, Appleton & Lange, 1991, pp. 945–958. Copyright 1991, The McGraw-Hill Companies, Inc. Used with permission.Panel B adapted from LeVay S, Stryker MP, Shatz CJ: "Ocular Dominance Columns and Their Development in Layer IV of the Cat's Visual Cortex: A Quantitative Study." Journal of Comparative Neurology 179:223–244, 1978. Used with permission.Panel C reprinted from Purves D, Augustine GJ, Fitzpatrick D, et al. (eds): Neuroscience. Sunderland, MA, Sinauer Associates, 1997, p. 427. Used with permission.Panels D and E reprinted from Hubel DH, Wiesel TN, LeVay S: "Plasticity of Ocular Dominance Columns in Monkey Striate Cortex." Philosophical Transactions of the Royal Society of London—Series B: Biological Sciences 278:377–409, 1977. Used with permission.

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