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

peak blood ethano l concentrations o f 15 0 mg/dl) provide
unique insight into the controversy over the con -
tribution o f th e V Z an d S Z t o th e populatio n o f
neocortical neurons. Dail y neuronal production dur -
ing th e firs t hal f o f the perio d o f neuronongenesis is
depressed b y prenata l exposur e t o ethano l (Miller ,
1986, 1988) . Durin g thi s time, th e V Z i s the promi -
nent neocortica l proliferativ e zone . Change s i n cell
proliferation withi n the V Z paralle l the earl y reduc -
tions i n neurona l generation . Prenata l exposur e t o
ethanol reduce s th e tota l numbe r o f cell s an d th e
number of cycling cells in the VZ (Miller, 1989) an d
it increases the time cells need t o transit through th e
cell cycle (Miller and Nowkowski, 1991).
The ethanol-induce d late surge in neuronal generation
occur s when the S Z becomes th e predominant
proliferative zone . The S Z i s affected b y ethanol i n a
way opposit e tha t o f th e VZ . Th e tota l numbe r o f
cells i n th e S Z an d th e numbe r o f cycling cells ar e
increased b y ethano l (Miller , 1989 ; Mille r an d
Nowakowski, 1991) .
Taken together , th e correlativ e dat a o n th e birt h
dates o f cortica l neuron s an d characteristic s o f V Z
and S Z cells show that both the VZ and S Z produc e
neurons. Thi s thesi s wa s tested i n a n experimen t i n
which fetuses were exposed t o ethanol for only 4 days
during th e perio d o f (a ) S Z prominenc e (betwee n
G18 an d G21) , (b ) VZ prominenc e (betwee n G1 2
and G15) , o r (c ) ste m cel l productio n (betwee n G 6
and G9) (Miller, 1996a). SZ cell proliferation and the
production o f late-generate d neuron s ar e onl y af -
fected whe n th e ethano l exposur e occur s betwee n
G18 an d G2 1 (Fig . 11-3) . Moreover, this late exposure
t o ethano l increase s both cel l proliferatio n an d
production. VZ cell proliferation and early-generated
neurons, b y contrast , ar e maximall y affected b y exposure
t o ethano l tha t occur s betwee n G1 2 an d
Gl 5, i.e., when the VZ is most prominent. This exposure
to ethanol inhibit s VZ cel l proliferatio n an d re -
duces th e numbe r o f neuron s generate d o n G15 .
Exposure to ethanol between G6 and G9 does not affect
th e proliferatio n o f cell s i n eithe r proliferativ e
zone o r th e numbe r o f early- or late-generate d neu -
rons. Furthermore , base d o n timing , i t appear s tha t
the VZ gives rise to neurons distributed in infragranu -
lar corte x an d th e S Z generate s supragranula r
neurons. This conclusion i s supported b y the tracin g
of derivative s of cell s tha t expres s transcripts fo r th e
genes Svetl (Tarabyki n e t al. , 2001 ) an d eux (Niet o
ETHANOL AND PROLIFERATION OF NEURONA L PRECURSORS 18 5
et al. , 2004 ) fro m th e S Z t o th e supragranula r laminae.
Radial Glia. Radia l glia, thought to serve as guides
for neurona l migratio n (Rakic , 1971 , 1978) , ar e
among th e first cortical cell s t o be generated . Tradi -
tionally, radial glia have been considered transitiona l
astrocytes (e.g. , Schmeche l an d Rakic , 1979 ; L u
et al, 1980 ; Voigt, 1989 ; d e Lima e t al, 1997) , how -
ever, mor e recen t evidenc e show s that som e radia l
glia ca n differentiat e int o neuron s (Malatest a e t al. ,
2000; Hartfuss et al, 2001; Levers et al, 2001; Noctor
et al , 2001 , 2002 ; Alvarez-Buyll a an d Garcia -
Verdugo, 2002; Gôtz e t al., 2002; Sanai et al, 2004).
This dual lineage is consistent with glial expression of
nestin, a cytoskeleta l protein associate d with neural
stem cell s (Hockfiel d an d McKay , 1985 ; Miller an d
Robertson, 1993) . Although n o studie s have directly
assessed th e effect s o f ethanol o n th e proliferatio n of
radial glia , it appears that th e periodicit y of the net -
work o f radia l glia l fiber s i s unaffecte d b y ethano l
(Miller an d Robertson , 1993 ; Vallè s e t al , 1996 ;
Minana e t al., 2000). This finding implies that these
cells proliferat e t o maintai n a consisten t densit y
within the expandin g telencephalic vesicle. A discussion
o f the effect s o f ethanol o n radia l glia and thei r
role in neuronal migratio n is provided in Chapter 3.
Hippocampal Formation
Neurons in the hippoeampal formation are generated
over a protracted period of time: i n the rat , from G1 5
to adulthoo d (Altman , 1962 ; Angevine , 1965 ; Sch -
lessinger e t al , 1978 ; Bayer , 1980 ; Miller , 1995a) .
Most neuron s i n th e thre e hippoeampa l fields ,
CA1-CA3, and th e dentat e gyru s are generated pre -
natally. The sit e of origin of these neurons is the VZ .
A notable exception is that most (-85%) granule neurons
i n th e dentat e gyru s ar e generate d postnatally .
Postnatal granule cell generation occurs in the IHZ.
Hippocampal cel l number s ar e substantiall y affected
by ethanol exposure. These effects ar e spatially
and temporally defined. Total DN A and protein con -
tent i n hippoeampa l formatio n i s lowe r i n animal s
exposed to ethanol prenatally (Miller, 1996b). I n contrast,
postnatal exposur e increases both DNA and protein
content. Anatomical studies have provided mor e
detailed informatio n o n thes e ethanol-induce d
effects. Animal s expose d t o ethano l prenatall y have