SYNAPTIC PLASTICITY: PHYSIOLOGY AND NEUROLOGICAL DISEASE - Synaptic Plasticity: New Research - page 10

reductions in Aβ have also been found in PS1 x APP mice [Oksman et al., 2006] and in 3 x
Tg mice [Green et al., 2007]. In the study by Ma and colleagues (2007), DHA significantly
increased LR11 protein levels in aged non-transgenic mice and in DHA-depleted transgenic
(APPsw) AD mice. This observation may help explain epidemiology suggesting reduced AD
risk associated with increased fish consumption and lower n-6/n-3 fatty acid ratios [Morris et
al., 2003; Kalmijn e t al., 2004].
Protein trafficking
Endosomes are believed to be major sorting stations in the endocytotic process, sending
proteins and lipids to multiple destinations including the cell surface, Golgi complex and
lysosomes [Murk et al., 2003]. Kennedy and Ehlers (2006) have described protein trafficking
to and from the postsynaptic membrane as a key mechanism underlying various forms of
synaptic plasticity. Ehlers (2000) demonstrated that AMPA receptor sorting occurs early in
endosomes and is regulated by synaptic activity and activation of AMPA and NMDA
receptors. It has also been suggested that stores of receptors are maintained intracellularly, in
organelles capable of rapid delivery to synapses [Ehlers, 2000; Carroll et al., 2001; Sheng and
Lee, 2001]. Endocytosis and exocytosis serve important roles in LTP and long-term
depression at hippocampal synapses [Luscher et al., 1999; Shi et al., 1999; Cooney et al.,
2002]. Blocking exocytosis prevents the induction of LTP, whereas blocking endocytosis
prevents the induction of long-term depression. Endosomes may indeed provide a local store
of receptors at individual dendritic spines. However, relatively little is known about the
distribution of endosomal organelles in distal dendrites where most synapses are located
[Luscher and Frerking, 2001]. The recent observations of Park et al. (2006) that spine
expansion is trafficked from recycling endosomes that reside locally at the spines themselves
suggests that agents which stimulate endocytosis and dendritic spine structure [Popov et al.,
2008] may promote synaptic plasticity.
Kinases and synaptic plasticity
Extracellular signal-regulated kinases
Extracellular signal-regulated kinases (ERKs) are members of the MAPK superfamily
and form a major signal transduction pathway mediating extracellular stimuli to the nucleus
[Schaeffer and Weber, 1999]. Originally discovered as regulators of cell division and
differentiation, an important role of the ERK signaling pathway is also evident in synaptic
plasticity, learning and memory [Impey et al., 1999; Sweatt, 2004; Thomas and Huganir,
2004]. For example, ERK activation is required for hippocampal LTP induction [English and
Sweatt, 1996; Atkins et al., 1998; Kanterewicz et al., 2000]. Behavioral studies have also
demonstrated a major role of ERK in long-term memory [Atkins et al., 1998; Blum et al.,
1999]. These findings, however, lack a direct link which proves a relationship between LTP
and memory. ERK1 and ERK2 display a high degree of sequence homology and share a
similar substrate profile [Boulton et al., 1991], and are solely activated by MAPK kinases
(MEKs). In the analysis of ERK signaling, most experiments use MEK inhibitors because no
specific ERK inhibitors are available, and these do not distinguish between MEK isoforms,
making it difficult to dissect the specific contribution of each isoform to physiological