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

58 NORMA L DEVELOPMENT
membrane protei n wit h its target SNARES , synaptosomal
associated protein (SNAP) 25 and syntaxin, was
the first identified and is the most widely known (Sollner
e t al. , 1993 ; Pevsne r e t al. , 1994) . Syntaxins , i n
turn, ca n bind t o either Muncl S o r Muncl3 in th e
presynaptic gri d to modulat e th e primin g event s for
vesicle fusion (Hat a et al., 1993 ; Asher y et al, 2000 ;
Misura et al, 2000). SNAP-25 binding by synaptotagmin
i n th e vesicl e membran e appear s t o regulat e
subsequent fusio n por e openin g durin g calcium -
dependent exocytosi s (Jorgensen et al. , 1995 ; Sugit a
and Sudhof, 2000; Littleton e t al, 2001).
ECM protein s such as laminins, collagens, and proteoglycans
are found i n and aroun d th e synapti c clef t
(Dityatev an d Schachner , 2003) . As with othe r adhe -
sive junctions, the density within the synaptic cleft con -
tains CAMs such as Ng-CAM and N-cadherin (Chavi s
and Westbrook , 2001; Phillips et al, 2001; Schuster et
al., 2001; Guan an d Rao, 2003). Members o f receptorligand
families such as Eph-ephrins and th e neurexinneuroligins
ar e als o presen t (Scheiffel e e t al, 2000 ;
Henderson e t al, 2001; Dean e t al, 2003; Grunwald
et al. , 2004) . Transmembran e protease s suc h a s
metalloprotease-disintegrins cleave the ectodomains of
these transynapti c molecule s t o attenuat e signalin g
(Tanaka e t al, 2000 ; Matsumoto-Miya i e t al. , 2003) .
Other extracellula r proteases such as plasminogen activators
can degrade components o f the ECM i n a manner
suspecte d to permit morphological change s a t the
synapse durin g development an d plasticit y (reviewed
in Dityatev and Schachner, 2003 ; Berardi et al, 2004).
In th e postsynapse , the PS D comprise s a number
of signaling and scaffolding molecules for receptors in
the plasm a membrane (Wals h and Kuruc, 1992 ; Walikonis
et al, 2000; Kim and Sheng, 2004; Peng et al,
2004; Phillips et al, 2004; Collins e t al, 2005). One
quintessential componen t i s PSD-95 , a membe r o f
the PSD/synapse-associate d protein/membrane -
associated guanylate kinase family of scaffolding mol -
ecules. I t is typically found at excitatory synapses an d
directly bind s transmembran e component s suc h a s
the N-methyl-D-aspartate receptor (NMDAR ) neuroligin,
as well as molecules involve d in secondary signaling
suc h a s neurona l nitri c oxid e synthetas e an d
regulatory proteins such as synaptic guanidine triphos -
photase activatin g protei n fo r Ra s (Iri e e t al. , 1997 ;
Kim and Sheng , 2004) . Similarly, glutamate receptor -
interacting protei n interact s with th e oc-amino -
3-hydroxy-5-methyl-4-isoxazole propionat e recepto r
(AMPAR) an d gephyri n wit h th e glycin e recepto r
(Meyer e t al, 1995 ; Don g e t al, 1997 ; Lev i e t al. ,
2004). Th e cytoskeleta l protein s acti n an d spectri n
concentrate a t both th e pré - and postsynapse . These
proteins, alon g wit h tubulin , ar e though t t o under -
lie th e characteristi c filamentou s appearanc e o f th e
postsynaptic we b an d ma y contribut e t o change s i n
postsynaptic recepto r compositio n durin g develop -
ment and plasticity (Matus et al., 1980 ; Fische r et al.,
2000; Ki m an d Lisman , 2001 ; W u e t al, 2002 ; re -
viewed in Moss and Smart, 2001; Luscher and Keller,
2004; van Zundert e t al, 2004).
Structural Correlates o f Synaps e
Assembly and Maturatio n
The pre - and postsynaptic elements of developing circuits
aris e principally from interaction s betwee n ax -
onal an d somatodendriti c filopodia . Axona l growt h
cones ma y form termina l bouton s a s they d o a t th e
neurornuscular junctio n (NMJ) , bu t predominantl y
form e n passant ("i n passing") along the lengt h o f an
axon (Bodian , 1968 ; Hind s an d Hinds , 1972 ; Skof f
and Hamburger , 1974 ; Vaugh n et al, 1977 ; Vaugh n
and Sims , 1978 ; Mason , 1982) . Coate d vesicle s and
smooth endoplasmi c reticulu m i n branchin g axon s
and coate d pit s near the postsynaptic densitie s o f nascent
contacts ma y participate i n traffickin g o f synaptic
components o r membrane recyclin g durin g early
periods o f synaptogenesi s (reviewe d i n Vaughn ,
1989). Eighty-nanomete r granulate d PTV s als o have
been foun d i n th e vicinit y of nascent synapse s (May
and Biscoe, 1973 ; Ahmari et al, 2000). Another char -
acteristic featur e o f man y immatur e synapse s i s a
reversed asymmetry, from th e earl y presence of presynaptic
vesicle s i n th e absenc e o f a pronounce d
PSD (Haye s and Roberts , 1973 ; Vaughn e t al, 1977 ;
Newman-Gage an d Westrum , 1984) . A s the synaps e
differentiates, the PSD thickens, at least at type I sites,
and presynapti c vesicle s steadil y increas e i n numbe r
(Bloom an d Aghajanian , 1966 , 1968 ; Jones , 1983 ;
Steward and Falk, 1986 ; Vaughn, 1989) .
Mechanisms o f Synapse Initiatio n
Spinal motor neuro n dendrite s arborize extensively as
they ente r th e margina l layer , a zone occupie d pro -
fusely b y axonal terminals (Vaughn et al., 1988) . Ob -
servations suc h a s thi s on e an d th e branchin g o f
dendritic filopodi a a t site s o f PSD-9 5 clusterin g
suggest a "synaptotropic " branchin g o f dendriti c