SYNAPTIC PLASTICITY: PHYSIOLOGY AND NEUROLOGICAL DISEASE - Synaptic Plasticity: New Research - page 11

function. ERK1 knockout mice do not show impairment in learning [Selcher et al., 2001], but
the embryonic lethality of ERK2 null knockout mice [Satoh et al., 2007] precludes similar
analyses. Utilizing a gene targeting technique, Satoh et al. (2007) have generated a series of
mice in which ERK2 expression decreased in an allele dose-dependent manner. Knockdown
mice in which ERK2 expression was partially (20-40%) reduced showed a deficit in long-
term memory as well as learning impairments [Satoh et al., 2007].
Long-term memory formation involves complex biochemical cascades leading to changes
in gene expression, accomplished partly by epigenetic mechanisms that remodel chromatin
[Tsankova et al., 2004], These include post-translational modifications of histones, which
regulate the dynamic interplay between the native inhibitory state of chromatin and a
transcriptionally active state [Jenuwein and Allis, 2001]. A number of studies suggest that
chromatin remodeling contributes to regulation of gene expression and neuronal function,
particularly in memory and synaptic plasticity [Guan et al., 2002; Korzus et al., 2004;
Levenson et al., 2004]. The regulation of histone phosphorylation is especially intriguing,
given the importance of the ERK/MAPK cascade in learning and memory. While ERK was
shown to regulate histone phosphorylation in hippocampal CA1 neurons [Levenson et al.,
2004], the precise downstream molecular mechanisms were not defined. One important
histone kinase that has been identified is mitogen- and stress-activated protein kinase-1
(MSK1), a nuclear kinase downstream of ERK/MAPK and p38/MAPK [Deak et al., 1998].
Although MSK1 appears to affect multiple targets important for plasticity and memory, its
role in role in behavioral learning remained largely unknown. A recent study now shows that
mice lacking MSK1 have deficits in multiple hippocampus-dependent tasks, and a selective
deficiency in histone H3 phosphorylation and acetylation, both markers of transcriptional
activation [Chwang et al., 2007].These results establish MSK1 as an important regulator of
hippocampal chromatin remodeling in long-term memory.
Glycogen synthase kinase-3
Glycogen synthase kinase-3 (GSK-3) is a ubiquitously expressed serine/threonine kinase
that is particularly abundant in the CNS [Woodgett, 1990]. GSK-3 phosphorylation substrates
include cytoskeletal proteins, transcription factors, and metabolic regulators, thus leading to a
prominent role for GSK-3 in cellular architecture, gene expression, and apoptosis among
others [Jope and Johnson, 2004]. This kinase may also play an important role in AD. Up-
regulation of GSK-3 by conditional induction [Hernandez et al., 2002; Engel et al., 2006] in
mice or by simultaneous inhibition of PI3K and PKC [Liu et al., 2003] in rats not only
induces tau hyperphosphorylation, but also impairs spatial learning any memory. Moreover,
two types of molecules approved for AD therapy, i.e. an inhibitor of acetylcholinesterase
[Scarpini et al., 2003] and an NMDA receptor antagonist [Reisberg et al., 2003] can increase
the serine inhibitory phosphorylation of GSK-3 in mouse brain and thus lead to the inhibition
of the kinase [De Sarno et al., 2006]. Collectively, these findings suggest that activation of
GSK-3 impairs learning and memory, whereas inhibition of GSK-3 reverses this effect. The
mechanism by which GSK-3 regulates learning and memory is not understood, although
impaired LTP may be a factor. Recent studies have shown that GSK-3 was inhibited during
LTP but activated during long-term depression [Peineau et al., 2007], and that conditional
expression of GSK-3 in mouse brain inhibited LTP [Hooper et al., 2007]. Using
pharmacological and genetic manipulations of GSK-3 activity, Zhu et al. (2007) have now
demonstrated that overactivation of GSK-3 inhibits the induction of LTP in rat hippocampus.