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DEVEL OPM ENT AND N EUR OBIOLO GY Assistant Editor: Paul j. Lombroso, M.D. Development of the Cerebral Cortex: 1. Forming the Cortical Structure PASKO RAKI C, M .D.• Se D .. AN D PAUL] . LOMBROSO. M .D. Lab or atories arou nd the world are explo ring th e intricacies of how the human central nervou s sys te m devel ops. U nde rstan d ing the mech an isms of corti cal d evel opment gives essential insight into the pathogenesis of man y genetic and acqu ired devel opm ent al p sychiatr ic di sorders. including autism. sch izo phrenia . and learning d isabilities. O ver th e next several months. this column will h ighlight aspe cts of normal and a b n o r ma l cort ica l developm ent. We will rep ort on recently isolat ed molecules th at have been di scovered to participate in br ain growth and devel opment. We will dis cuss the fu nc tio ns of th ese proteins and how mutations in them disrupt the normal developmental trajectory of the chi ld ren we see in our offices. N eurons o f the ce reb ral co rt ex form a highly organized lamin ar and radial str uct u re. The ad u lt human co rt ex is ch a rac te rized by six layer s. each co ns ist ing o f spe cial ized neurons with specific phenot ypes and syna ptic connections (Fig. IA ). Although in most o rgans . cells are born near their eve nt ual location. in th e embryonic de velopment of t he co rtex. neurons are generat ed some dist an ce awa y. The fin al m igration of the se neurons and the establishment of proper interneuronal connections are critical for proper cortical fun cti oning. Defects in this d ynamic proce ss underlie a number of developmental di sorders of higher bra in functi on. The first neurons dest in ed to settle in the human co rtex are produced during the first half of gestation. deep within the brain and close to the cavity of the cerebral ventricle in a region called the ventricular zone. Shortly after their last m itotic d ivision s. these neurons m igrate outward toward the pial surface of the cortex. where they form a sheet of cells called th e corti cal plate. Each su ccessive gen eration o f m igrating neurons passes through the previously born cells before arr iving a t the final de stination at the interface between the co rt ical plate and the marginal zone (Fig. I B). During migration. neuron s use a transient population of rad ial glial cells (Fig. IC) as a scaffold ing to aid thei r nav- c B A ~ PIal Surface -' Leading Process ~~~R Marglnal Layer , .,' Radial Cortical Plalo _ _ Radial Glial Process Glial Process - Ra al Migrating Cell- Mig sting Neuron Noel-Radially M'graling Co Tra Ing Process Racial Gil Ce Body ___ RadialG lia Ventricular Zone Fig . 1 Nor ma l developme nt of the cerebra l cortex. (Al Sect ion throug h the developin g pr im ate foreb rain sbowing d istrib uti on paHern of radial glial pro cesses th at spa n feta l cereb ral wall fro m the ventricle to the pial surface. (B ) Enlargement of the boxed area in (A) to illustra te how neu rons migr ate from th eir birth place in the vent ricular zone aero" the intermediate zone [0 their final destinatio n at the int erface betw een the marginal zone and th e develop ing conical plate. (C) Neuroblasts use the surface of elon gated rad ial glial fibers as a gu ide during their mig ration. From Raki c P ( )972). Mo de of cell m igration to the superfic ial layers of feral monkey neocortex. J Comp Neurol 1 4~:(' I -!U. copyright © 1972. Jo hn Wi ley & Sons. 116 J. AM . ACAD . C H ILD ADOLES C . PSYCHIATRY , .\7 :1, JAN UARY 19 98 DEV ELOPM ENT AND NE URO BI O LO GY igatio n. These cells form long fascicles that span the cerebr al cortex and guide the migrating neurons through each cortical layer. According to the radial unit hyp othesis of coni cal development, the horizontal location of con ical neuron is determined by the position of its precursor cells in the proliferative ventricular zone, while its depth result s from its birth order. Th is pattern of development has two major con sequences. First, the corte x develops in an inside-out pattern in which the earliest-born neurons are found in the deepest conical layers and th e later-born neurons mo ve to the m ore superficial layers. Second, the radial glial hypothesis provides an explan at ion for the columnar organi zation of the co rtex. Each group of progenitor cells with in the ventricular zone gives rise to a column of int errelated neu rons above it. After the neurons have taken th eir proper laminar position s, they devel op characteristic synapti c connections with ne arby neurons as well as more distant neur on s in associated region s of the co rtex. Di sruptions of neuron al m igrat ion have been found in several developmental disorders, such as lissencephaly and movement disorders (such as the reeler mutation in mice). The molecular basis for these disord ers will be discussed in the next two columns. In addition, more subtle disruptions of migration and in the development of synaptic connections J . AM . AC A D . C HI L D A D OI.ES C. PS YC H IATR Y, .H :1. J ANUA RY 19 98 have been proposed for more co mmo n di sorders such as dyslexia and psychosis. WEB SITE OF INTEREST h llp :ll info.m ed .yale.ed u/n euro biolr ak icl raki c. html (visit thi s sit e o n the Inte rne t d epicti ng anima ted version of cellula r events dur ing early cortical de velopm ent) ADDITIONAL READINGS H atten M (1993), T he role of migration in cent ral nervous system neuronal develop ment . Curr Opin Neurobiol.L~8-44 Levitt P. Barbe M . Eagleson K (1997), Patt ern ing and specificatio n o f th e cereb ral co rtex. Annu Ra Neurosci 20 :1-2 4 Mountcastle V (1997), The colum nar o rgan izatio n of the neoco rtex. Brain 120:70 1- 72 2 Rakic P (19 88) , Specification of cere bral con ical areas. Scimce 241 : 170-176 Rakic I' (1995), Radi al versu s tangent ial migratio n of neu ronal clones in the developing cereb ral cort ex. Proc Na t! A cad Sci 92 :11323-11.327 Acapu d july 25. 1997. Dr. Rakic is l'roJfssorand Chairman, N eurobiology, ~;dr Unit' rrsiry School of Medicine, Neio Ha ven, C T Dr. Lomb roso is Associat e Professor. Child Stu d,y Center. };dr Uui l'rrsiry School ofMedicine. Correspondence to Dr. Lombroso, Child Stltdy Center. Yale Uni versity School ofMedicine, 230 Sou th Frolllagr Road. Nr ui Haren, CT 06520. 0890-85 67/98/3701 - 0 116/ $0 .30 0 /01\)1998 by th e American Acad em y of C h ild and Ado lescent Psychia try. 117