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191
Journal of Pharmacological Sciences
©2005 The Japanese Pharmacological Society
Critical Review
J Pharmacol Sci 98, 191 – 197 (2005)
Hippocampus-Dependent Memory Formation: Do Memory
Type-Specific Mechanisms Exist?
Keiko Mizuno
1
and Karl Peter Giese
1,
*
1
Wolfson Institute for Biomedical Research, University College London, London, WC1E6BT, UK
Received April 13, 2005
Abstract. Long-term memory (LTM) formation requires gene transcription and de novo protein
synthesis. The transcription factor CREB is required for hippocampus-dependent LTM forma-
tion, and it is activated by several signaling pathways, including protein kinase A (PKA), the
mitogen activated protein/ extracellular signal-regulated kinases (MAPK or ERKs), and
Ca
2+
/ calmodulin kinases (CaMKs). However, it is unknown whether all types of hippocampus-
dependent LTM use the same signaling to activate transcription, and whether the transcriptional
output is the same. Here we present molecular genetic and behavioral studies to demonstrate that
two types of hippocampus-dependent LTM formation, spatial and contextual, require different
signaling molecules. This can be illustrated by the CaMK kinases, CaMKKα, and CaMKKβ,
which have converse roles. CaMKKα is required for contextual and CaMKKβ is required for
spatial LTM formation. This leads to the surprising conclusion that there are distinct types of
hippocampus-dependent LTM, which differ in their underlying molecular mechanisms.
Keywords: hippocampus, cAMP-responsive element binding protein, signaling,
Ca
2+
/ calmodulin kinase, mouse genetics
Introduction
The study of patient H.M. in the mid 1950s showed
that the formation of long-term memory (LTM) requires
the medial temporal lobe (brain areas including the
hippocampus, the amygdala, and part of the temporal
cortex). H.M. lost his ability to generate new LTM after
bilateral removal of the medial temporal lobe for treat-
ment of his severe seizures. Even though H.M. lost his
ability to generate new LTM, he kept his older memories
from before surgery, and he was able to have short-term
memory (STM). STM lasts for only a few minutes,
whereas LTM can last for days, weeks, or years. In
humans, LTM can be distinguished as explicit (declara-
tive) or implicit (non-declarative) memory. Explicit
memory is recalled by a deliberate and conscious effort,
such as factual knowledge of people, places, and things.
Implicit memory is involved in training, reflexive,
motor, and perceptual skills. The information from H.M.
and other similar patients have demonstrated an essential
role of the hippocampus in the formation of explicit but
not implicit memory. For example, H.M. can not
remember new faces and places, but he can learn new
motor skills (1). In rodents lesions of the hippocampus
impair memory for space and context, and the hippo-
campus is thought to be important for creating spatial
representations in the brain (2).
Using genetically modified mice, cellular and mole-
cular mechanisms underlying hippocampus-dependent
LTM formation have been studied intensively. Because
some genes such as N-methyl-
D-aspartate (NMDA)
receptors and the transcription factor cAMP-responsive
element binding protein (CREB) are needed for develop-
ment and survival, traditional null mutant mice are
not always suitable for studying mechanisms of LTM
formation. Therefore, some mutant mouse lines were
generated using the forebrain-specific αCaMKII-
promoter for spatial restriction, and occasionally, the
tetracycline-regulated system for temporal reversibility
in the expression of dominant-negative transgenes (3, 4).
Region-restricted deletions of genes, such as in CA1-
NR1-null mutant mice, were also generated using the
*Corresponding author. FAX: +44 207 916 5994
E-mail: p.giese@ucl.ac.uk
Invited article
K Mizuno and KP Giese192
phage P1-derived, Cre/ loxP recombination system
(Fig. 1).
Recently, the molecular genetic analysis of hippo-
campus-dependent LTM has shown that there are
distinct types, which require different signaling mole-
cules. Here we will review this evidence and focus on
studies that tested particular mutant mouse lines in both
the water maze and contextual conditioning and found
impaired LTM formation.
Different types of hippocampus-dependent behav-
ioral tasks
Several hippocampus-dependent LTM tasks exist, but
the water maze and contextual fear conditioning are the
most commonly used tasks in the field of mouse mole-
cular genetics.
1) Hippocampus-dependent spatial memory forma-
tion is frequently investigated in the hidden-platform
version of the water maze (5). In the water maze, mice
learn to navigate to a submerged platform by using
distal, spatial cues in the room. Mice are trained in serial
sessions and at the end of training, spatial memory
formation is assessed in a probe trial where the platform
is removed from the pool. If the mouse has formed
normal spatial memory, it will spend significant time in
the target quadrant where the platform was located. As a
control for performance deficits, a visible platform
version of this task is used, which does not require the
hippocampus. The water maze is a multi-trial task in
which mice learn slowly. It is impossible to distinguish
between impairment in learning versus memory with the
exception of a few particular LTM impairments (e.g., 6);
and furthermore over-training, depending on the training
protocol, could potentially miss the detection of an
abnormal phenotype.
Fig. 1. Genetic techniques to restrict mutations. Left: The tetracycline-dependent regulatory system is used for inducible
expression of a transgene. The tetracycline transactivator (tTA) is used as a switch ON/OFF transcription to drive the expression
of a gene of interest. A mouse line (Mouse A) that expresses tTA protein under a tissue-type specific promoter (αCaMKII), and a
mouse line (Mouse B) that expresses a gene of interest placed downstream of the tet operator (tetO) promoter are intercrossed.
The tTA protein binds to the tetO promoter and induces transcription. Whenever the tetracycline (doxycyclin DOX) is present in
either drinking water or foods, it blocks transcription. Right: Spatial restriction by the Cre/ loxP system is a widely used
technique. Cre is a site-specific DNA recombinase derived from the P1 bacteriophage and recognizes loxP sites. Cre catalyzes the
deletion of DNA that is flanked by a pair of loxP sites (floxed), creating a null mutation of the gene of interest. A mouse line
(Mouse A) that expresses Cre driven by a tissue-specific promoter (αCaMKII) and a mouse line (Mouse B) that contains the
floxed gene are intercrossed. Restricted expression of Cre such as expression only in the hippocampal area CA1 or CA3 leads to a
region-restricted deletion of the floxed gene.
Distinct Hippocampal Memory Types 193
2) Another frequently used task, contextual condition-
ing, is also hippocampus-dependent (7). In this task,
mice can learn a new environment (training box) as a
whole context, not as context elements. In contextual
conditioning, a mouse is exposed to a novel environ-
ment, which is the context. A mild foot shock is pro-
vided and consequently the mouse associates the context
with the shock. When placed back into the context, the
mouse remembers the context-shock association and
exhibits ‘freezing’. Freezing is scored at 1 – 2 h (protein
synthesis-independent, STM) and 24 h or longer time
points (protein synthesis-dependent, LTM) after the
training. Contextual conditioning with a tone presenta-
tion requires the dorsal hippocampus and amygdala and
also permits testing for amygdala-dependent tone fear
conditioning (8). If a particular mutant is impaired in
both contextual and tone conditioning tests, it is
impossible to establish whether the impaired contextual
memory formation resulted from dysfunction of either
the hippocampus or the amygdala. Another point to
consider is that in some mutants, contextual condition-
ing may be normal even in the presence of hippocampal
dysfunctions because non-hippocampal systems can
support contextual conditioning (7). In this case, context
discrimination, a more difficult task (9), may be more
sensitive and therefore detect impairments in hippo-
campus-dependent memory formation. On the other
hand, the contextual discrimination task may test for
another hippocampus-dependent memory type.
Molecular mechanisms of LTM formation
The process of LTM formation requires gene tran-
scription and de novo protein synthesis in contrast to
STM, which requires post-translational modification of
proteins (10). The transcription factor CREB is required
for hippocampus-dependent LTM formation (11); and
signaling by protein kinase A (PKA), the mitogen
activated protein/ extracellular signal-regulated kinases
(MAPK/ ERKs), and Ca
2+
/ calmodulin kinases (CaMKs)
have been implicated in activation of CREB, by phos-
phorylating Serine 133. The transcriptional co-activator
CREB-binding protein (CBP) also needs to be phos-
phorylated to activate CREB-mediated transcription
(11, 12). CBP plays a role in cognitive function not
only as a platform protein, but also as a chromatin
remodelling histone acetyltransferase (13). The current
view of LTM formation in the hippocampus involves an
activation of CREB and CBP. However, it is unknown
whether all types of hippocampus-dependent LTM use
the same signaling to activate transcription and whether
the transcriptional output is the same.
Common signaling for hippocampus-dependent
spatial and contextual LTM formation
Several molecular genetic studies have shown that
there is common signaling between spatial and contex-
tual LTM formation.
CREB was the first transcription factor to be studied
intensively in LTM formation. CREB hypomorphic
mutant mice have impairments in both spatial and
contextual LTM formation (14). However, even though
these mutants lack expression of the predominant α- and
δ-isoforms of CREB, they have a compensatory up-
regulation in CREB β and the cAMP-responsive element
modulator (CREM) (15). Additional mutants with
inducible expression of a dominant inhibitor of all
CREB/ ATF transcription factors confirmed a role for
CREB in LTM formation (16, 17). Although CREB is
important for LTM formation, the phenotypes of the
CREB hypomorphic mutants and some other CREB-
specific transgenic manipulations are inconsistent. We
believe that this is due to the large number of
CREB/ ATF transcription factors including CREM and
ATF-1 being expressed in the hippocampus. There is a
tight regulation between these transcription factors,
probably depending on the genetic background, which
influences the behavioral phenotype.
Among the CREB-activating kinases, some
Ca
2+
/ calmodulin-dependent protein kinases (CaMKs)
directly connect Ca
2+
-signaling and gene expression
(12, 18). One of these kinases is CaMKIV, which
phosphorylates CREB, and has a relatively well-studied
role in hippocampal LTM. Forebrain-restricted domi-
nant-negative CaMKIV mutant mice (dnCaMKIV) are
impaired in spatial and contextual memory formation
(19). Contextual memory is impaired 7 days, but not
1 day after conditioning, and the impairment in contex-
tual LTM formation does not seem to be caused by
amygdala dysfunction. This is because memory of cued
conditioning is not affected. In contrast with these
findings, CaMKIV null mutant mice have been
described as normal in spatial memory formation (20).
However, the testing conditions may not have been
sufficiently sensitive to detect an abnormal phenotype.
The CaMKIV null mutants are impaired in contextual
memory formation, but this impairment is likely to have
resulted from amygdala dysfunction because the mutants
are also affected in cued conditioning (21).
The neuronal response to a Ca
2+
stimulus is a complex
process involving direct Ca
2+
/ calmodulin (CaM) actions
as well as secondary activation of multiple signaling
pathways such as cAMP and ERK (12, 18). Transgenic
mice, expressing a dominant inhibitor of CaM selec-
tively in the nuclei of adult forebrain neurons, are
K Mizuno and KP Giese194
impaired in contextual memory 1 day but not 1 h after
conditioning LTM formation (22). These mutants are
also impaired in spatial memory formation.
The MAP kinase pathway contains at least three
protein kinases: the extracellular signal-regulated kinases
1/ 2 (ERK1 and ERK2), the immediate upstream of the
MAP/ERK kinase (MEK or MKK), and the Raf family
as MEKK (23). Conditional transgenic mice expressing
dominant-negative MEK1 in the postnatal forebrain are
impaired in contextual memory 1 day but not 1 h after
conditioning LTM formation (24). These mutants are
also impaired in spatial memory formation.
The cAMP-PKA pathway is involved in CREB acti-
vation. Dominant-negative PKA mutants have impaired
LTM but normal STM in contextual and cued condition-
ing, and impaired spatial memory formation (25).
The role of c-Fos, an immediate-early gene and a
target gene of CREB, was studied in conventional c-fos
null mutants, but these mice suffer from developmental
malformations (26) and are not suitable for studying
learning and memory. A CNS-specific c-fos null mutant
(c-fos δ
CNS
) is impaired in both spatial and contextual
LTM formation (27). However, interestingly when the
fos-related antigen 1 (Fra-1), a member of c-fos family
of transcription factors, was knocked-in into the c-fos
locus, it can only replace the function of contextual, but
not spatial memory formation (28). This suggests that
there are different molecular requirements for spatial
and contextual LTM formation.
Molecules required for either spatial or contextual
LTM
Recent findings show that spatial and contextual LTM
require for their formation different signaling to regu-
late gene transcription and they need distinct transcrip-
tional outputs. The Ca
2+
/ calmodulin kinase kinases,
CaMKKα and CaMKKβ, can both phosphorylate
CaMKIV and this phoshorylation event enhances
CaMKIV activity (18). Studies with CaMKKβ null
mutants revealed that this kinase is required for the
activation of CREB by spatial training as well as spatial
memory formation in the water maze in male mice (29).
However, CaMKKβ is not needed for contextual LTM
formation. Thus, for spatial but not contextual LTM
formation, CaMKKβ may activate CaMKIV to phos-
phorylate CREB. In contrast to CaMKKβ, CaMKKα is
required for contextual but not spatial LTM in male mice
(30). The requirement for contextual LTM is hippo-
campus-dependent because CaMKKα is not needed for
cued conditioning. It remains to be investigated whether
CaMKKα activates CaMKIV to phosphorylate CREB
during contextual but not spatial LTM formation. The
studies with CaMKKα and CaMKKβ mutants show
that there is a double dissociation for the signaling
mechanisms required for spatial and contextual LTM
formation. This dissociation between spatial and
contextual LTM formation has also been observed in
several other mutant mouse lines.
Earlier studies of CREB in LTM formation focused
only on CREB. However, CREB can heterodimerize
with the other CREB family transcription factors CREM
and ATF1, and their functions are not restricted to
hippocampus-dependent memory formation (12). To
overcome these difficulties, a transgenic mouse line
expressing KCREB was generated. KCREB is a mutant
of human CREB that is a potent dominant-negative
inhibitor, and importantly, it also inhibits all three CREB
family transcription factors. dCA1-KCREB mice have
restricted expression of KCREB in area CA1 of the
dorsal hippocampus (17). These mutants are impaired in
spatial LTM formation, but have normal contextual
LTM. Importantly, when the KCREB gene is switched
off, spatial LTM impairment is rescued. Furthermore,
dorsally restricted dCA1-KCREB provided evidences
that the dorsal hippocampus is needed for spatial LTM,
but not contextual LTM. These results support previous
lesion studies that total hippocampal lesions disrupt both
the water maze and contextual fear conditioning,
whereas ventral lesions disrupt fear conditioning while
sparing performance in the water maze (31), and dorsal
hippocampal lesions disrupt performance in the water
maze only (32). A similar phenotype, impaired spatial
and normal contextual LTM, was observed in brain-
specific CREB null mutants, which have up-regulated
CREM expression (33).
CBP is an important factor to form LTM and func-
tions as a transcriptional co-activator as well as histone
acetyltransferase (HAT), which can remodel the chro-
matin structure. Dominant-negative CBP transgenic
mice that specifically lack HAT activity (CBP{HAT-})
are impaired in spatial memory formation but they are
normal in contextual LTM (34).
As one of the mechanisms to stimulate ERK, the
PKA-dependent activation of the Ras-related small
G protein Rap1 and B-Raf were identified. Transgenic
mice expressing a temporally controlled dominant-
negative Rap1 (iRap1) in the forebrain showed that
Rap1 is required for spatial memory formation (35).
Mice with iRap1 exhibit deficits in contextual discrimi-
nation but not in contextual and cued fear conditioning
tasks.
The pituitary adenylate cyclase activating polypeptide
(PACAP) type I receptor (PAC1) is a G-protein coupled
receptor. Null mutants as well as forebrain-specific
mutants both have a deficit in contextual but not cued
Distinct Hippocampal Memory Types 195
fear conditioning, but normal spatial LTM (36).
Brain-derived neurotrophic factor (BDNF) is a target
gene of CREB (37). BDNF expression is regulated in the
hippocampus after spatial training as well as contextual
conditioning (38, 39). Since BDNF and its receptor
TrkB are expressed throughout the brain from develop-
ment, it is difficult to know the function specifically in
learning and memory using traditional null mutants. To
study the specific role of BDNF, forebrain-restricted
BDNF null mutants (Emx-BDNFKO mice) were
generated (40). Emx-BDNFKO mice are impaired in
spatial memory formation but they are normal in contex-
tual LTM. However, in these BDNF mutants, contextual
freezing was enhanced in comparison to WT mice,
and the mutants generalize their context-shock associa-
tion to other contexts. Thus, there is the possibility that
contextual learning in mutant mice is not hippocampus-
dependent. Indeed pre-training lesions suggest that
“contextual conditioning” can occur without the hippo-
campus, possibly resulting from discrete cue-shock
associations (9).
Conclusion
The transcription factor CREB was recognised as a
molecular switch for LTM formation in the hippo-
campus. Original findings suggested that CREB is
required for LTM formation in general. However, some
difficulties were encountered in these earlier experi-
ments to elucidate the detailed roles of CREB in
different types of LTM formation. Using region-specific
mutations, recent results suggest that not only CREB
but also other transcription factors might be important
for LTM formation. CREB is more involved in spatial
LTM formation, but perhaps other transcription factors
are required for contextual LTM formation. For
example, c-Rel, a transcription factor of the nuclear
factor κB family, is required in contextual LTM forma-
tion (41). Further supporting this idea, we found that
CREB activation was regulated during spatial LTM
formation and required CaMKKβ (29), but we failed to
detect any CREB activation during contextual LTM
formation (our unpublished data). This might suggest
Fig. 2. Summary of the signaling pathways involved in spatial and/ or contextual long-term memory (LTM) formation
discussed in this review. Excitatory neurotransmitters, ligands for GPCRs, and neuronal growth factors are among the stimuli
that activate signaling pathways during hippocampus-dependent LTM formation. It is thought that these signals activate CREB
kinases and CREB. Stimulus-dependent kinases include PKA, CaMKIV, and downstream-kinases of ERK such as pp90RSK
(RSK), and MSK families of protein kinases are CREB kinases. Some signaling components are required for both spatial and
contextual LTM formation (circled) and others are required for either spatial or contextual LTM formation (boxed). Abbrevia-
tions: AC: adenylate cyclase, BDNF: brain-derived neurotrophic factor, CaM: Ca
2+
/calmodulin, CaMKK: Ca
2+
/calmodulin
kinase kinase, CBP: CREB binding protein, CTX: contextual LTM formation, ERK: extracellular signal-regulated kinase,
GPCR: G protein-couple receptor, MEK: MAP/ ERK kinase, NMDAR: N-methyl-
D-aspartate receptor, PAC1: PACAP type I
receptor, PKA: cAMP-dependent protein kinase, RTK: receptor tyrosine kinase, VSCC: voltage-sensitive calcium channels.
K Mizuno and KP Giese196
that contextual LTM formation requires another tran-
scription factor(s) and CaMKKα.
We have discussed the signaling molecules whose
roles in spatial and contextual LTM formation has been
tested using genetically modified mice and this is
summarised in Fig. 2. It seems that molecules upstream
of CREB are differentially required for distinct types of
hippocampus-dependent LTM; CaMKKβ and Rap1 are
involved in spatial, whereas CaMKKα and PAC1 are
needed for in contextual LTM formation. Therefore, we
conclude that the formation of two types of hippo-
campus-dependent LTM, spatial and contextual, uses
different signaling molecules and perhaps distinct
transcription factors.
Acknowledgments
We thank L. Drinkwater for helpful comments and are
grateful for the generous support from the Wellcome
Trust and British Medical Research Council.
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