MINIREVIEW
Transducer ofregulatedCREBandlatephase long-term
synaptic potentiation
Hao Wu, Yang Zhou and Zhi-Qi Xiong
Institute of Neuroscience and Key Laboratory of Neurobiology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences,
Shanghai, China
Introduction
Synaptic plasticity, the change in the strength of neur-
onal connections in the brain, is thought to underlie
learning and memory [1–3], and may play a crucial role
in the pathogenesis of a variety of neurological disor-
ders, including drug addiction [4]. One form of synaptic
plasticity that has received much attention is long-term
potentiation (LTP), an activity-dependent long-lasting
increase ofsynaptic strength [5]. Like memory, LTP
can be divided into two distinct phases: an early phase
(E-LTP) which lasts only minutes to few hours and
involves modification of preexisting proteins; and a late
phase (L-LTP), which persists from hours to days and
requires gene transcription and protein synthesis [6].
Despite the fact that LTP was discovered by Bliss
et al. [7] more than three decades ago, the molecular
and cellular mechanisms underlying this phenomenon
are still not well understood. One major advance in
this effort occurred when the properties of N-methyl-
d-aspartate-type glutamate receptors (NMADR) were
first elucidated in the mid-1980s, and at about the
same time, researchers found that N-methyl-d-aspar-
tate receptor (NMDAR) antagonists prevented LTP.
NMDAR act as detectors of the coincidence between
the depolarization of postsynaptic membrane and
the presence of glutamate in the synaptic cleft. The
resulting Ca
2+
transients result in LTP [8–10]. A
likely molecular cascade is that Ca
2+
influx through
NMDAR activates one or more protein kinases in the
postsynaptic neuron such as Ca
2+
⁄ calmodulin-depend-
ent protein kinases II and IV, protein kinase (PK)A,
PKC, and mitogen-activated protein kinase, etc. [11].
Activation of these kinases induces gene expression
Keywords
CREB; hippocampus; LTP; TORCs
Correspondence
Z Q. Xiong, Laboratory of Neurobiology of
Disease, Institute of Neuroscience, Chinese
Academy of Sciences, 320 Yue Yang Road,
Shanghai 200031, China
Fax: +86 21 5492 1735
Tel: +86 21 5492 1716
E-mail: xiongzhiqi@ion.ac.cn
(Received 28 January 2007, revised 29 April
2007, accepted 8 May 2007)
doi:10.1111/j.1742-4658.2007.05891.x
In the central nervous system, long-term adaptive responses to changes in
the environment, such as the processes involved in learning and memory,
require the conversion of extracellular stimuli into intracellular signals.
Many of these signals involve the induction of gene expression. The late,
transcription- and translation-dependent phaseoflong-term synaptic
potentiation (L-LTP) is an attractive cellular model for long-lasting mem-
ory formation. The transcription factor cAMP response element-binding
protein (CREB) plays an essential role in the maintenance of L-LTP. How-
ever, how synaptic signals propagate to the nucleus to initiate CREB-target
gene expression is unclear. Recent studies indicate that the CREB transdu-
cer ofregulatedCREB activity 1 coactivator undergoes neuronal activity-
dependent translocation from the cytoplasm to the nucleus, a process
required for CRE-dependent gene expression and the maintenance of
L-LTP in the hippocampus.
Abbreviations
BDNF, brain derived neurotrophic factor; bZIP, basic leucine zipper; CRE, cAMP response element; CREB, CRE-binding protein; CBP, CREB-
binding protein; DN, dominant-negative; KID, kinase inducible domain; LTP, long-term potentiation; NMDAR, N-methyl-
D-aspartate receptor;
PK, protein kinase; SIK, salt inducible kinase; VGCC, voltage-gated calcium channel.
3218 FEBS Journal 274 (2007) 3218–3223 ª 2007 The Authors Journal compilation ª 2007 FEBS
and synthesis of new proteins, a process required for
cAMP response element (CRE)-dependent gene expres-
sion and L-LTP.
Role of CREB-target gene expression
in L-LTP
Pharmacological evidence demonstrated that the
expression of L-LTP in hippocampus requires both
gene transcription and protein synthesis [12–14]. Fur-
ther study indicated that the induction of L-LTP corre-
lates with the expression of CRE-dependent gene
expression [15]. Although some studies argued against
the role ofCREB in hippocampal L-LTP and memory
formation [16,17], accumulating evidence from both
invertebrates and vertebrates has demonstrated the
essential role ofCREB in mediating hippocampal
L-LTP and memory process [15,18–21]. Overexpressing
a constitutively active form ofCREB (VP16-CREB)
facilitates hippocampal L-LTP induction probably via
increased BDNF (brain derived neurotrophic factor)
expression [22,23]. One well established mechanism for
CREB-mediated gene transcription is that upon being
phosphorylated at Ser133, CREB undergoes conforma-
tional change and recruits CREB binding protein
(CBP) and other elements to initiate target gene tran-
scription [3,24].
Although studies have demonstrated the importance
of CREB phosphorylation, in particular at Ser133, for
CRE-driven gene transcription [3,25], stimuli which
induce Ser133 phosphorylation do not completely par-
allel CREB dependent transcription [15]. Some extra-
cellular stimuli are capable of phosphorylating CREB
at Ser133 but fail to trigger CREB-target gene tran-
scription [26–29]. Moreover, the inconsistent kinetics
between CREB Ser133 phosphorylation and CREB-
dependent gene transcription has also been reported.
That is, although persistent phosphorylation was
observed following membrane-depolarizing stimulation
in primary cortical neurons, an in vitro nuclear run-on
assay showed that CREB-dependent gene transcription
only occurs in a short time window, implicating the
existence of a switch-off mechanism in controlling
the kinetics of gene expression other than Ser133
phosphorylation [30].These findings suggest at least
one additional factor is involved in the regulating
CRE-target gene transcription.
Transducers ofregulatedCREB activity
(TORCs)
With respect to the structure–function relationship of
CREB activity, it was shown that deletion of the basic
lucine zipper (bZIP) domain ofCREB remarkably
inhibited CRE-target gene expression [29,31], suggest-
ing that a modulatory mechanism works via this
domain. Indeed, phylogenic analysis of the cDNAs of
CREB gene from Caenorhabditis elegans to mammals
indicates that the primary amino acid sequence of
CREB is highly conserved in at least two domains,
namely kinase inducible domain (KID) and bZIP
DNA binding ⁄ dimmerization domain [32]. KID in
CREB, encompassing Ser133 site, binds to CBP in a
phosphorylation-dependent manner [33]. Studies from
CBP mutant mice showed that CBP is critical for the
late-phase of hippocampal LTP and some forms of
long-term memory [34].
Efforts to identify novel CREB coactivators through
bZIP domain led to the discovery of a conserved fam-
ily of coactivators: TORCs. TORC family proteins are
capable of binding with the bZIP domain independent
of phosphorylation status ofCREB at Ser133, and to
specifically potentiate CRE-mediated reporter gene
transcription [35,36]. In the mammalian genome, the
TORC family consists of three members, TORC1,
TORC2 and TORC3 [35,36]. Its Drosophila homolog
dTORC was identified via database searching [36] and
has been shown to function similar to its mammalian
counterparts [37]. Whereas there are no extensive
homologies among three mammalian TORCs, a highly
conserved N-terminal coiled coil domain can be
mapped to each member and this domain is respon-
sible for tetramer formation and for CREB activity
potentiation [35]. Recently, it was found that TORC2
is a key regulator of fasting glucose metabolism,
thereby shedding light on a long-standing puzzle in
which insulin and glucagon can equally induce canon-
ical CREB phosphorylation, but have opposite effects
on CREB-target gene transcription and glucose meta-
bolism [38,39]. Most recently, it has also been reported
that TORCs are critical for the mitochondrial biogen-
esis in muscle cells [40].
Gene profiling analyses showed that mRNA levels
of three TORCs are differentially expressed in distinct
tissues [35]. To gain insight into the potential function
of TORCs in the central nervous system, we cloned
the TORC isoforms from the adult rat brain and
found both TORC1 mRNA and protein are abundant
in the hippocampus [41]. Consistent with earlier studies
with TORC2 which translocates into nucleus in
response to elevated intracellular cAMP and ⁄ or cal-
cium [42], nuclear accumulation of TORC1 could be
induced by increasing intracellular cAMP level, Ca
2+
influx via voltage-gated calcium channel (VGCC)
or activation of NMDAR in primary hippocampal
neurons [41].
H. Wu et al. Transducers ofregulatedCREB activity
FEBS Journal 274 (2007) 3218–3223 ª 2007 The Authors Journal compilation ª 2007 FEBS 3219
Regulation of CREB-dependent gene
transcription and hippocampal L-LTP
by TORC1
The nuclear translocation property of TORC1 makes
it an attractive candidate in relaying signals from syn-
apse to nucleus elicited by neuronal activity [43]. We
used CRE-reporter gene assay to examine the func-
tional consequence of neuronal activity-dependent
TORC1 nuclear accumulation. Overexpressing a dom-
inant-negative (DN) TORC1 or knockdown of endo-
genous TORC1 inhibits neuronal activity-dependent
expression of CRE-reporter gene; whereas overexpress-
ing the wild-type (WT) TORC1 increases both basal
and neuronal activity-induced CRE-reporter gene
expression. The expression of endogenous BDNF, a
well-known CREB target gene [30] implicated in the
synaptic plasticity [44], is also up-regulated by TORC1
[41].
Since CRE-target gene expression is critical for the
maintenance of L-LTP [23], we thus tested the func-
tional role of TORC1 in L-LTP in the Shaffer collat-
eral pathway of rat hippocampal slices. This pathway
is derived from axons that project from the CA3
region to the CA1 region and is utilized extensively to
study NMDA receptor-dependent LTP. E-LTP in this
pathway can be induced by one train of high frequency
stimulation and lasts approximately 1 h; L-LTP can be
induced by three or four trains of high frequency sti-
mulation and lasts more than 3 h. Using this model,
AB
C
Fig. 1. Activity-dependent nuclear translocation of TORC1 contributes to L-LTP maintenance. (A) Subcellular distribution of TORC1 in CA1
neurons after basal stimulation (Basal), E-LTP induction (one train of high frequency stimuation, 1 · HFS) and L-LTP induction (four trains of
high frequency stimulation, 4 · HFS). Distribution of TORC1 was examined by immunohistochemical staining. L-LTP induction induces nuc-
lear and perinuclear accumulation of TORC1 in CA1 neurons. (B). DN-TORC1 infection blocks L-LTP maintenance in hippocampal slices.
Induction of L-LTP was marked with four arrowheads. Maintenance of L-LTP was evaluated by comparing the field excitatory postsynaptic
potential (fEPSP) slope before L-LTP induction (as indicated at the zero point of x-axis by ‘1’) with the fEPSP slope 180 min after L-LTP
induction (as indicated by ‘2’). Typical traces of fEPSP at time point ‘1’ and ‘2’ are shown in the upper panel. (C). WT-TORC1 infection low-
ered the threshold for L-LTP induction in hippocampal slices. Induction of E-LTP is marked by an arrowhead. fEPSP of time point ‘1’ and ‘2’
was compared for evaluation of E-LTP or L-LTP.
Transducers ofregulatedCREB activity H. Wu et al.
3220 FEBS Journal 274 (2007) 3218–3223 ª 2007 The Authors Journal compilation ª 2007 FEBS
we found that the induction of L-LTP, but not E-LTP,
triggers robust nuclear and perinuclear accumulation
of TORC1 in the CA1 neurons of hippocampal slices
(Fig. 1A). Studies of the phosphorylation level of
CREB after the same stimulation protocols revealed
that remarkable phospho-CREB was induced only
after E-LTP but not after L-LTP. Thus, nuclear accu-
mulation of TORC1, but not CREB phosphorylation,
correlates with L-LTP induction in hippocampal slices
[15,41]. We further found that overexpressing the
DN-TORC1 suppressed the maintenance of L-LTP
without affecting E-LTP, whereas overexpressing the
wild-type form of TORC1 facilitated the induction of
L-LTP (Fig. 1B). Most recently, another independent
study also revealed TORC1 is required for the syner-
gistic activation of CREB-mediated transcription by
Ca
2+
and cAMP and the maintenance of L-LTP [45].
In this work, Kovacs et al. [45] generated a membrane
permeable peptide of dominant-negative TORC1. They
found that acute delivery of TORC1 dominant-negat-
ive peptide into rat hippocampal slices blocked the
maintenance of L-LTP induced by three trains of high
frequency stimulation. Taken together, these findings
indicate that TORC1 acts as the coincidence detector
for sensing intracellular Ca
2+
and cAMP changes
induced by neuronal activity and is translocated to
nucleus to drive CREB-target gene transcription and
maintain L-LTP (Fig. 2).
Perspectives
In the central nervous system, activity-regulated
CREB-target gene transcription has been implicated in
diverse processes, ranging from neuronal development
and synaptic plasticity to disease conditions [3]. It
would be interesting to investigate whether and to
what extent TORC1 participates in these processes. If
so, subsequent efforts to reveal the dynamic regulation
of TORC1 activity should have therapeutic impli-
cations for a lot of neurological disorders. Since the
subcellular distribution of TORCs is dependent on its
phosphorylation status [42], an interesting question is
what types of kinase and ⁄ or phosphatase are respon-
sible for this shuttling process of TORC1 in neurons.
In cell line, salt inducible kinase (SIK) and protein
phosphatase calcineurin regulate the phosphorylation
status of TORC2 [42]. Preliminary results showed that
SIK mRNA could be readily detected from the hippo-
campus (Y F. Li & Z Q. Xiong, unpublished data)
and calcineurin was also found to be enriched in neu-
rons [46]. Thus, it is most likely that SIKs and cal-
cineurin may be the primary candidates regulating its
phosphorylation status in response to neuronal activ-
ity. However, the involvement of other kinases or
phophatases in regulation of TORC1 activity is also
possible. Efforts to identify these kinases ⁄ phosphatases
will provide more insight into the regulation of TORC
function in the nervous system.
Earlier studies reported that CREB target genes
including c-fos, BDNF and Nur ⁄ 77 are transcribed
only in a transient manner, whereas CREB phosphory-
lation at Ser133 persists for more than 6 h [30], sug-
gesting the existence of additional molecule element
regulate the kinetics of CREB-target gene transcription
A
B
Fig. 2. Neuronal signaling promotes nuclear accumulation of
TORC1 and BDNF expression and maintenance of L-LTP. (A). The
schematic drawing shows that Ca
2+
influx via VGCC or NMDAR or
increased level of intracellular cAMP can promote nuclear accumu-
lation of TORC1, and nuclear TORC1 acts as a CREB coactivator to
potentiate the expression ofCREB target gene BDNF in neurons.
(B) The schematic drawing shows that TORC1 nuclear accumula-
tion activates transcription of CRE-target genes in neurons, thus
leads to potential ofsynaptic transmission.
H. Wu et al. Transducers ofregulatedCREB activity
FEBS Journal 274 (2007) 3218–3223 ª 2007 The Authors Journal compilation ª 2007 FEBS 3221
bypass CREB phosphorylation in neurons. Interest-
ingly, detailed analysis about dynamics of the nuclear
translocation of TORC1 showed that nuclear accumu-
lation of TORC1 peaks at 1 h and returns to basal
level approximately 6 h following member-depolarizing
stimulation in cortical neurons (Y F. Li & Z Q.
Xiong, unpublished data), which correlates well with
the transcription kinetics of the CREB target gene.
Further work to delineate the contribution of CREB
phosphorylation versus nuclear translocation of
TORC1 to the transcription kinetics of CREB-target
gene expression will help our understanding the regula-
tory mechanisms of neuronal activity-dependent CRE-
target gene expression and the role in neuronal devel-
opment andsynaptic plasticity.
Acknowledgements
We thank Ms Ye-Fei Li for her help with the artwork.
The authors’ work is supported by the National Basic
Research Program of China Grant (2006CB806600),
the Key State Research Program of China Grant
(2006CB943900), national ‘863’ high-tech research and
development program (2006AA02Z166), and ‘Hundred
Talents Plan’ of the Chinese Academy of Sciences and
Shanghai Pujiang Program Grant (05PJ14114).
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H. Wu et al. Transducers ofregulatedCREB activity
FEBS Journal 274 (2007) 3218–3223 ª 2007 The Authors Journal compilation ª 2007 FEBS 3223
. MINIREVIEW Transducer of regulated CREB and late phase long-term synaptic potentiation Hao Wu, Yang Zhou and Zhi-Qi Xiong Institute of Neuroscience and Key Laboratory of Neurobiology, Shanghai. transcription. Transducers of regulated CREB activity (TORCs) With respect to the structure–function relationship of CREB activity, it was shown that deletion of the basic lucine zipper (bZIP) domain of CREB. intracellular signals. Many of these signals involve the induction of gene expression. The late, transcription- and translation-dependent phase of long-term synaptic potentiation (L-LTP) is an