Brain Development: Normal Processes and the Effects of Alcohol ...

4 INTRODUCTIO N
been pursued . Indeed , wor k o n ethano l provide s a
model o f how t o stud y the negativ e effect s o f othe r
substances. Moreover , study of the effect s o f ethanol
provides a uniqu e insigh t int o norma l development .
The approac h of this book is to look at three contrast -
ing situations: normal development, an d the effect s of
two different type s of challenges. Examinatio n o f th e
normal and abnormal situations informs each of these
situations. Thus, i t is only through geneti c an d envi -
ronmental challenge s tha t a ful l appreciatio n o f th e
complexity of brain development can be achieved.
NORMAL DEVELOPMEN T
Our understandin g o f norma l neura l developmen t
has progressed by quanta during the las t dozen years .
Not onl y hav e w e begu n t o understan d th e myria d
genes tha t ar e expresse d i n th e developin g centra l
nervous syste m (CNS) , bu t function s fo r th e tran -
scripts and th e protein s have been ascribed . Two examples
ar e rln an d dix, gene s tha t cod e fo r protein s
important in stopping neuronal migration and in promoting
the migration of neocortical loca l circuit neurons
from th e ganglion eminence .
The compellin g abnorma l organizatio n o f th e
brain an d th e associate d dysfunctio n o f th e reeler
mouse hav e fascinate d developmenta l neurobiolo -
gists for more than five decades (e.g. , Falconer, 1951 ;
Alter et al, 1968; Bruc k and Williams, 1970 ; Lambert
de Rouvroit and Goffinet , 1998) . The invers e organi -
zation o f the reele r mous e ha s provide d uniqu e in -
sights int o mechanism s o f normal neurogenesi s an d
the formatio n of neural networks. Yet it is only since
1995 that the genetic basi s for this murine mutant has
been discovered , the knockout of the gen e rln (D'Arcangelo
e t al. , 1995 ; Hirotsun e e t al. , 1995 ; Ogaw a
et al. , 1995) . Th e functio n o f th e gen e product ,
reelin, continues to be debated.
The gen e dix i s a key player i n cortica l develop -
ment (Marin and Rubenstein , 2003). It is critical for
the generatio n o f loca l circui t neuron s i n th e gan -
glionic eminence. A dearth of local circuit neurons is
evident i n dix knockou t mice . Thus , a ne w doo r t o
understanding th e complexit y o f cortica l neurono -
genesis an d tangentia l pathway s o f neuronal migra -
tion has been opened .
The section on normal development describes our
current understandin g o f cellula r an d molecula r
events tha t defin e developmenta l phenomena . Fo r
convenience, neural development has been divided
into four phases : cel l proliferation , migration, differ -
entiation, and deat h (Chapter s 2, 3 , 4, an d 5 and 6 ,
respectively). Althoug h thes e ar e discret e phases ,
they are highly integrated. That is, the number o f cycling
cells ha s a direc t effec t o n th e wa y in whic h
cells differentiate and on the incidence o f cell death.
Thus, these chapter s address a single developmental
phase whil e placin g ontogeneti c event s i n th e con -
text o f the continuu m o f neural development. I n a
provocative essa y (Chapter 7 ) at the en d o f this sec -
tion, basic information on ontogeneti c event s is discussed
i n term s o f mammalian evolution , an d thei r
ramifications o n th e respons e of the nervou s system
are addressed.
ETHANOL-AFFECTED DEVELOPMEN T
The concep t that ethano l affect s th e developmen t of
the mammalia n (human ) brain came t o the for e i n
1973 wit h th e publicatio n o f paper s b y Jone s an d
Smith (Jone s an d Smith , 1973 ; Jone s e t al, 1973) .
These were not the first papers to identity fetal alcoho l
effects. Thoug h les s celebrated , report s b y Lemoin e
and colleagues (1968) and Ulleland (1972) had already
described feature s o f feta l alcoho l syndrom e (FAS) .
Although it has been suggeste d that the first evidence
linking alcoho l consumptio n durin g pregnanc y an d
deleterious effect s o n offsprin g come s fro m Gree k
and Roma n mytholog y an d fro m th e Bible , this no -
tion was debunked by Abel (1984).
To the best of my knowledge, the first documentation
o f someone wit h FA S can b e attribute d t o th e
artists Harvey Kurtzman in 195 4 and Norman Ming o
in 1956 . The y dre w a perso n originall y known as
Melvin Coznowsk i o r Me l Haney , late r know n a s
Alfred E . Neuman (also spelled Newman). 1 Mr. Neuman
ha s al l o f the classi c pathomnemonic craniofa -
cial malformation s of FAS (thin uppe r lip, deficient,
philtrum, narro w palpebrai fissures, flattened bridge
of th e nose , an d lo w set ears) , alon g wit h acknowl -
edged menta l dysfunctio n and probabl e intrauterine
growth retardation (a s evidenced b y microencephaly).
Although verificatio n o f prenata l exposur e i s un -
known, such evidence i s not obligatory for a diagnosis
of FAS (Stratton e t al., 1996) . As is typical of accomplished
artists, Kurtzman and Ming o were perceptive
observers and mad e associations that were as insightful
a s thos e o f th e experience d pediatrician s wh o