Biology Reference
In-Depth Information
C
ELL
A
DHESION
M
OLECULES AND
S
YNAPTIC
S
TRUCTURE
Cell adhesion molecules of the immunoglobulin and and cadherin superfamilies have a
wide range of functions during development. For example, in the nervous system they play
roles in cell migration, axonal growth and guidance, and synapse formation [Walsh and
Doherty, 1997]. The neural cell adhesion molecule (NCAM), a member of the
immunoglobulin superfamily is a membrane-associated glycoprotein expressed on the surface
of neurons and glial cells, and plays a key role in nervous system development [Goodman,
1996] and synaptic plasticity in relation to learning and memory consolidation [Schachner,
1997; Benson
et al.,
2000; Venero
et al.,
2006]. Although initially thought to function by
modulating adhesion between cells, it is now clear that some cell adhesion molecule functions
require the activation of specific second messenger signaling cascades in cells. For example,
there is now substantial evidence that NCAM, N-cadherin, and L1 signal via a direct
interaction with the fibroblast growth factor receptor (FGFR) [Williams
et al.,
1994, 2001;
Saffell
et al.,
1997; Sanchez-Heras
et al.,
2006]. A number of studies have shown that FGFR
and NCAM are involved in learning and memory consolidation [Cremer
et al.,
1994; Sasaki
et al.,
1999]. A peptide (FGL) mimicking the heterophilic binding of NCAM to FGFR1 has
been identified [Kiselyov
et al.,
2003] which increases the length of neurites from rat
embryonic hippocampal neurons with a bell-shaped concentration-response curve
characteristic of growth factor-induced neuritogenesis. This stimulatory response can be
blocked with an antibody against FGFR, indicating that the NCAM-derived FGL peptide is
an agonist of the FGFR [Kiselyov
et al.,
2003; Neiiendam
et al.,
2004]. FGL improves
cognitive function through enhancement of synaptic function [Cambon
et al.,
2004]. Whereas
FGL mimetic did not affect synaptic or spine density in the hippocampus of aged rats, it did
induce significant structural alterations in synapses and dendritic spines [Popov
et al.,
2008].
These findings indicate that the behavioural changes reported previously following FGL
peptide treatment may be at least partially driven by structural modifications in synapses and
dendritic spines in hippocampus.
Neurotrophins, astrocytes and dendritic spine plasticity
Neurotrophic factors are secreted proteins that promote neurite outgrowth, neuronal cell
differentiation and survival both
in vivo
and
in vitro
. The neurotrophins are a gene family of
neurotrophic factors that were identified as promoters of neuronal survival, but it is now
appreciated that they regulate many aspects of neuronal development and function, including
synapse formation and synaptic plasticity [Sofroniew
et al.,
2001; Chao
et al.,
2003; Lu and
Woo, 2005; Reichardt, 2006]. The first neurotrophin, nerve growth factor (NGF), was
discovered during a search for survival factors that could explain the deleterious effects of
deletion of target tissues on the subsequent survival of motor and sensory neurons [Levi-
Montalcini, 1987]. NGF is part of the neurotrophin family of polypeptides which function as
homodimers, and which share a high degree of structural homology and includes brain-
derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4)
[Ibáñez, 1994]. The neurotrophins interact with two entirely distinct classes of receptors,
p75
NTR
and Trks (tropomyosin receptor kinases). The former was initially identified as a low-
