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Memory storage consists of a short-term phase that is independent of new protein synthesis and a long-term
phase that requires the synthesis of new proteins and RNA. A cellular representation of these two phases
has been demonstrated recently for long-term potentiation (LTP) in both the Schaffer collateral and the
mossy fibers of the hippocampus, a structure widely thought to contribute to memory consolidation. By
contrast, much less information is available about the medial perforant pathway (MPP), one of the major
inputs to the hippocampus. Both a short-lasting and a long-lasting potentiation (L-LTP) can
be induced in the MPP of rat hippocampal slices by applying repeated tetanization in reduced levels of
magnesium. This potentiation is dependent on the activation of NMDA receptors. The early, transient
phase of LTP in the MPP does not require either protein or RNA synthesis, and it is independent of protein
kinase A (See Drosophila PKA) activation. By contrast, L-LTP required the synthesis of proteins and RNA, and is selectively
blocked by inhibitors of cAMP-dependent protein kinase (PKA). Forskolin, an adenylate cyclase activator,
also induced a L-LTP that was attenuated by inhibition of transcription. These results demonstrate that, like
LTP in the Schaffer collateral and mossy fiber pathways, MPP LTP also consists of a late phase that is
dependent on protein and RNA synthesis and PKA activity. Thus, cAMP-mediated transcription appears to
be a common mechanism for the late form of LTP in all three pathways within the hippocampus (Nguyen, 1996).
Activation of the Ca2+- and calmodulin-dependent protein kinase II (CaMKII) and its conversion into a persistently activated form by
autophosphorylation are thought to be crucial events underlying the induction of long-term potentiation (LTP) by increases in postsynaptic
Ca2+. Because increases in Ca2+ can also activate protein phosphatases that oppose persistent CaMKII activation, LTP induction may also
require activation of signaling pathways that suppress protein phosphatase activation. Because the adenylyl cyclase (AC)-protein kinase A
signaling pathway may provide a mechanism for suppressing protein phosphatase activation, the effects of AC activators on
activity-dependent changes in synaptic strength and on levels of autophosphorylated alphaCaMKII (Thr286) were investigated. In the CA1 region of
hippocampal slices, briefly elevating extracellular Ca2+ induces an activity-dependent, transient potentiation of synaptic transmission that
can be converted into a persistent potentiation by the addition of phosphatase inhibitors or AC activators. To examine activity-dependent
changes in alphaCaMKII autophosphorylation, electrical presynaptic fiber stimulation was replaced with an increase in extracellular K+ to
achieve a more global synaptic activation during perfusion of high Ca2+ solutions. In the presence of the AC activator forskolin or the protein
phosphatase inhibitor calyculin A, this treatment induces an LTP-like synaptic potentiation and a persistent increase in autophosphorylated
alphaCaMKII levels. In the absence of forskolin or calyculin A, it has no lasting effect on synaptic strength and induces a persistent decrease
in autophosphorylated alphaCaMKII levels. These results suggest that AC activation facilitates LTP induction by suppressing protein
phosphatases and enabling a persistent increase in the levels of autophosphorylated CaMKII (Makhinson, 1999).
Activation of adenylyl cyclase and the consequent production of cAMP is a process that has been
shown to be central to invertebrate model systems of information storage. In the vertebrate brain, it has
been suggested that a presynaptic cascade involving Ca influx, cAMP production, and subsequent
activation of cAMP-dependent protein kinase is necessary for induction of long-term potentiation
(LTP) at the cerebellar parallel fiber-Purkinje cell synapse. It has been suggested that use-dependent modification of the strength of the parallel fiber-Purkinje cell synapse in the cerebellar cortex is necessary for certain forms of motor learning, including adaptation of the vestibulo-ocular reflex and associative eyeblink conditioning. One cellular model system that has been proposed as a mechanism for such information storage is cerebellar long-term depression (LTD), in which coactivation of climbing fiber and parallel fiber inputs to a
Purkinje cell induces a persistent, input-specific depression of the parallel fiber-Purkinje cell synapse. The converse phenomenon, cerebellar LTP, has also
been described. In this protocol, the parallel fiber-Purkinje cell synapse is strengthened by repetitive
parallel fiber stimulation at low (2-8 Hz) frequencies, thus endowing this
synapse with the important capacity of use-dependent bidirectional modification.
Mutant mice in which the major Ca-sensitive adenylyl cyclase isoform of cerebellar cortex (type I) is deleted have been used to show that activation of cAMP-dependent protein kinase
results in an 65% reduction in cerebellar Ca-sensitive cyclase activity and a nearly complete
blockade of cerebellar LTP, assessed by using granule cell-Purkinje cell pairs in culture. This blockade is
not accompanied by alterations in a number of basal electrophysiological parameters and may be
bypassed by application of an exogenous cAMP analog, suggesting that it results specifically from
deletion of the type I adenylyl cyclase (Storm, 1998).
The electrophysiological findings reported here are consistent with a previously proposed model for
hippocampal mossy fiber-CA3
and cerebellar LTP induction. In this model, Ca
influx through presynaptic voltage-gated channels activates a Ca/CaM-sensitive adenylyl cyclase,
resulting in production of cAMP, activation of PKA, and the consequent phosphorylation of proteins
that control synaptic strength. PKA could conceivably exert its effect either locally, in the presynaptic
terminal, or at other sites through activation of cascades linked to a diffusable messenger. However,
several findings have been proposed in support of the hypothesis that the locus of cerebellar LTP
expression is presynaptic. Cerebellar LTP expression is associated with a decrease in the rate of
synaptic failures when measured in granule cell-Purkinje cell pairs. In addition, it is associated with a decrease in paired-pulse facilitation. Perhaps the most convincing evidence for a presynaptic
locus of expression comes from work in cell culture that takes advantage of the fact that the rapid
inward current produced in glial cells by activation of adjacent granule cells is 90% mediated by
activation of AMPA/kainate receptors and 10% by electrogenic glutamate re-uptake. Stimulation
of the granule neuron can give rise to the LTP of either the total glial synaptic current
or the pharamacologically isolated glial re-uptake current. LTP recorded using
either of these detector currents has properties indistinguishable from that of granule neuron-Purkinje
neuron LTP, as seen in the current study. Therefore, the site of the adenylyl cyclase and PKA action that produces LTP is almost certainly presynaptic (Storm, 1998).
A secondary finding from this study shows that while several measures of
motor coordination were unaltered in AC1 mutant mice, rotorod performance is impaired. The rotorod test measures the ability of an animal to maintain balance by coordinating the movement
of all four feet and making the necessary postural adjustments. It also measures the animal's ability to
improve on these skills with practice. Mutant and wild-type mice were examined for
rotorod performance using two test protocols: rod rotation at a constant rate of 10 rpm,
and rod acceleration from 10 to 18 rpm over a 2 min period. The AC1 mutant mice have
a significant performance deficit that is evident in the first trial in both constant velocity and
accelerating conditions. While both wild-type and AC1 mutant animals were able to improve their
performance with repeated trials, aspects of this improvement differed. The
wild-type mice showed continual improvement, reaching asymptotic performance at about trial 10-12.
The AC1 mutant mice showed no improvement during the first four trials, but were able to improve
their performance thereafter. However, their asymptotic performance is significantly below that of
the wild types. In contrast, AC8 mutant mice showed normal performance in these rotorod tasks. Unfortunately, it is not possible to analyze this
complex phenotype in terms of motor coordination versus motor learning. One possibility is that a
defect in motor coordin ation alone underlies this behavior. For example, in initial trials the AC1
mutant may not have been able to stay on the rod long enough to get much practice time. Thus, it is
possible that in the AC1 mutant mouse a performance defect is simply masking normal learning (in
much the same way that a three-legged mouse might be expected to learn slowly, improve, but
ultimately perform suboptimally in this task). Alternatively, it should be considered that "initial"
performance in a rotorod task is only initial with respect to this training session. The defect in initial
performance could, at least in part, represent a learning deficit for motor experience prior to the first
rotorod trial (Storm, 1998).
The mechanism(s) responsible for PKA enhancement of
neurotransmitter release have not been elucidated but may involve direct phosphorylation of proteins of
the secretory machinery. Treatment of cultured cerebellar granule cells with forskolin or cAMP
analogs results in an increase in presynaptic vesicular cycling as detected using an
immunocytochemical technique. Forskolin or cAMP analogs do not affect resting Ca levels in cultured hippocampal neurons, and these drugs can potentiate transmitter release evoked directly by ruthenium red. More recently, Forskolin-induced potentiation of the parallel fiber-Purkinje cells
EPSC is not associated with alterations in intraterminal resting Ca, evoked Ca influx, or changes in the
presynaptic fiber volley, but is associated with an increase in mEPSC frequency. Taken together, these
studies suggest that the effect of increasing intraterminal cAMP on the probability of release can be
completely accounted for by changes in the secretory machinery. The hypothesis that PKA activation
exerts its effects on release through alteration of secretory machinery is particularly appealing because
the synaptic vesicle protein Rab3A, which is an effector for the PKA substrate rabphilin 3, is essential
for hippocampal mossy fiber LTP (Storm, 1998 and references).
Adenylyl cyclases (ACs) are involved in a variety of advanced CNS functions, including some types of learning and memory. At
least nine AC isoforms are expressed in the brain: they are divisible into three broad classes based on the ability of Ca2+ to
modulate their activity. This study examined the hypothesis that different learning tasks would differentially activate ACs in selected
brain regions. The ability of forskolin (FK) or Ca2+ to enhance AC activity in the hippocampus, parietal cortex, striatum, and cerebellum
was examined after mice had been trained in either a spatial or procedural learning task using a Morris water maze.
The training apparatus was a 1.5 m diameter pool filled with water that was heated to 27°C and made
opaque with white Createx, a nontoxic latex paint. The pool was surrounded by numerous visual cues that were kept in constant
locations during the entire training period. The mice were trained in either a spatial learning task or a procedural learning
task. In either case, the animal had to swim until it located an escape platform that was submerged ~0.5 cm below the
surface of the water. For the spatial learning task, the escape platform was placed in the 'center' of one of four imaginary quadrants
of the pool and kept in this location throughout training. For the procedural learning task, the location of the platform was randomly
varied between the four quadrants but was always placed in the center of the quadrant.
Sensitivity of
ACs to forskolin is enhanced to a greater degree in most brain regions after procedural learning, but Ca2+-sensitive ACs in the
hippocampus are more sensitive to spatial learning. Because nonspecific behavioral elements, such as stress or motor activity,
are similar in both experimental tasks, these results provide the first evidence that acquisition of different kinds of learning is
associated with selective changes in particular AC species in a mammalian brain and support the idea that different biochemical
processing, involving particular isoforms of ACs, subserves different memory systems (Guillou, 1999).
Accumulating data have provided evidence that memory is not a unitary entity but is organized in multiple systems involving distinct
brain areas or circuitries. Several dual theories suggest a selective role for the hippocampus in a
higher-order form of memory, such as spatial learning, declarative memory, or processes underlying the establishment of relational representations. In contrast, hippocampal-independent mechanisms posited to be involved in simpler forms of
learning have been suggested to bring into play brain structures involved in the motor function, such the striatum and the cerebellum.
The present findings are in agreement with the idea of multiple memory systems in the sense that learning-related changes in AC activity
depend on the brain region, the task, and the type of AC itself. For example, increases in FK modulation of AC activity
occur after either spatial or procedural training in the hippocampus, striatum, and cerebellum but not after spatial training in the
parietal cortex. In all brain regions, procedural training produce a larger increase in the sensitivity of
ACs to FK than does spatial training. A very different pattern of results is observed for Ca2+-sensitive ACs. In this case, neither
type of training alters the response to Ca2+ in the parietal cortex. No response in Ca2+-sensitive AC activity is observed after
spatial training in the cerebellum. In the striatum, both types of training alter the response of ACs from inhibiting to enhancing
activity. However, whereas procedural training produces a larger enhancement than spatial training in the response of Ca2+-sensitive ACs in the striatum and cerebellum, the opposite result is seen in the hippocampus. Notwithstanding the
differences just described, it is clear that either spatial or procedural training results in overlap in the types of changes observed in
AC activity. This result is not unexpected, because it is unlikely that these two complex learning tasks rely entirely on a single
memory system (Guillou, 1999).
The results of several studies using lesion techniques have suggested a role for parietal cortex in spatial learning or memory. In this context, it is noteworthy that the present study did not reveal any alterations in AC activity in the parietal
cortex after spatial learning. Because it is unlikely that learning in this task did not, to at least some extent, involve parietal areas, it is reasonable to conclude that ACs do not play a critical role in spatial information processing
by the parietal cortex (Guillou, 1999 and references).
Messenger RNA for AC5, a cyclase normally inhibited by Ca2+, has been shown to be selectively
localized in striatal neurons. In agreement with others, it was observed that
striatal AC activity is inhibited by Ca2+ in control mice but not in mice that have been trained in either the spatial or the procedural
task. The experimental design precludes a trivial explanation for this finding, such as circadian changes in basal levels of AC5
activity. Low levels of AC1 and AC8 messenger RNA have also been detected in the striatum. Although it is likely that expression of these ACs is enhanced by the behavioral
experience, it is also possible that Ca2+-stimulated ACs localized presynaptically in corticostriatal inputs are affected by training.
Because several Ca2+-sensitive AC isoforms are present in the striatum, it seems reasonable to suggest that behavioral experience
produces a differential change in one of these, such as AC1 or AC5. Further studies will be necessary to resolve this issue (Guillou, 1999 and references).
On the whole, it was found that the AC activity is enhanced after both procedural and spatial learning, with lower amplitudes after
the latter. One could therefore argue that both tasks rely on similar types of processing and hence induced similar changes in AC
activity. The quantitative variation in the biochemical results could, in this case, be attributed to differences between the mastery of
the task in the two training conditions. However, the results show that, in the hippocampus, the changes in AC activity are also
qualitative and depend on the type of stimulation used. AC activity measured in the presence of FK, a nonselective stimulator of the
AC types, was found to be more greatly increased after procedural training, whereas Ca2+-stimulated activity (type-selective) was
more greatly increased after spatial training. Because hippocampal Ca2+-stimulated AC activity is also increased in the
procedural group, two possibilities must be considered to explain the differential results for the two training paradigms.
(1) It is possible that the activity of both Ca2+-stimulated and Ca2+-insensitive ACs are increased after procedural training,
whereas only Ca2+-stimulated ACs are affected by spatial training. Latent spatial learning could also explain why the activity of
Ca2+-sensitive ACs in the hippocampus is higher in the procedural group than in naive controls. This would suggest a specific
role for hippocampal Ca2+-stimulated ACs (AC1 and/or AC8) in spatial information processing and is consistent with the
hypothesized common role for Ca2+-stimulated ACs in mammals and invertebrates. (2) Changes in
both Ca2+-insensitive and Ca2+-stimulated ACs may have taken place in both learning paradigms, but the direction of change in
one group of ACs is different from in the other (Guillou, 1999 and references).
Basal AC activity in the hippocampus is not different after spatial and procedural learning, although opposite changes were
revealed in a dose-dependent manner by FK and Ca2+ stimulation, respectively. Because the forskolin signal reflects both
Ca2+--insensitive and Ca2+-sensitive activity, a specific explanation for this observation is that one or several Ca2+-insensitive AC
isoforms are downregulated by spatial learning. This possibility is in accordance with earlier results showing a decrease in
FK-stimulated hippocampal AC activity (in the absence of change in the basal AC activity) after training in a radial arm maze
spatial discrimination task. Thus, the favored explanation is that Ca2+-stimulated ACs are
enhanced by spatial learning in the hippocampus, whereas Ca2+-insensitive ACs are decreased.
AC1 (Ca2+-stimulated) and AC2 (Ca2+-insensitive) are both dominantly expressed in the hippocampus. AC1 has been suggested
to be a good candidate for involvement in neuroplasticity mechanisms, in agreement with a role in long-term potentiation. The present results, showing an enhanced sensitivity of the hippocampal AC activity to
Ca2+ after spatial training, support the idea that AC1 could be a key molecule involved in the spatial mapping function of the
hippocampal formation. However, AC2 is the obvious candidate for downregulation after spatial learning. Yet it
was recently found that messenger RNA for AC9 is also highly concentrated in the hippocampal formation. Interestingly, AC9 is indirectly inhibited by Ca2+ via the activation of calcineurin. Little is
currently known about precise subcellular locations of ACs. However, if AC1 and AC9 are colocalized in the hippocampal
neurons, as is likely to be the case, one would expect that increases in intracellular concentrations of Ca2+ would activate AC1
while inhibiting AC9. If cAMP is an essential signal for neuroplasticity mechanisms to take place and to allow spatial learning,
inhibitory effects of Ca2+ on AC9 activity should be inactivated. Therefore, a decrease of AC9 expression and/or its functionality
might be expected during spatial learning (Guillou, 1999 and references).
It is hypothesized that Ca2+ stimulation of calmodulin (CaM)-activated
adenylyl cyclases (AC1 or AC8) generates cAMP signals critical for late phase
LTP (L-LTP) and long-term memory (LTM). However, mice lacking either AC1 or AC8
exhibit normal L-LTP and LTM. However, mice lacking both enzymes (DKO) do not
exhibit L-LTP or LTM. To determine if these defects are due to a loss of cAMP
increases in the hippocampus, DKO mice were unilaterally cannulated to deliver
forskolin. Administration of forskolin to area CA1 before training restores
normal LTM. It is concluded that Ca2+-stimulated adenylyl cyclase activity is
essential for L-LTP and LTM and that AC1 or AC8 can produce the necessary cAMP
signal (Wong, 1999).
It was hypothesized that lack of L-LTP and the memory defects are due to the
loss of Ca2+ stimulation of adenylyl cyclase in area CA1 of the hippocampus.
This interpretation is supported by experiments showing that administration
of forskolin to area CA1 restores normal L-LTP and passive avoidance memory to
DKO mice. In these experiments, forskolin increases cAMP levels in area CA1 on
the cannulated-side of the hippocampus because of the presence of other
forskolin-stimulated adenylyl cyclases in DKO mice. The recovery of L-LTP and LTM
in DKO mice by administration of forskolin to area CA1 suggests that cAMP can
play a permissive role for neuronal plasticity and that activation of other
pathways (e.g., the Erk/MAP kinase pathway) may provide the anatomic specificity
required for L-LTP and LTM. This is consistent with recent studies implicating
the Erk/MAP kinase pathway for Ca2+ activation of the CREB/CRE transcriptional
pathway, L-LTP, and LTM (Impey, 1998). Treatment by forskolin alone can rescue L-LTP and LTM
in the DKO mice because cAMP activates Erk/MAP kinase in neurons. The results
from this study, however, do not preclude mechanisms wherein L-LTP and LTM arise
from coactivation of the cAMP and Erk/MAP kinase pathways at specific synapses.
It seems likely that the cAMP and Erk/MAP kinase pathways are costimulated in a
synaptic specific manner by Ca2+ during L-LTP and LTM (Wong, 1999 and
references).
It is interesting that LTM for passive avoidance learning was restored to
DKO mice when forskolin was administered by unilateral cannulation of the
hippocampus. It is believed that cAMP is increased in only one half of the
hippocampus in these experiments because administration of fluorescent-labeled
forskolin shows no diffusion of the drug to the noncannulated side of the
brain. Furthermore, CRE-mediated transcription is only increased by forskolin
right below the cannulation site. This suggests that the mice remember passive
avoidance training when cAMP increases are generated in only one-half of the
hippocampus, providing that other signal transduction pathways are intact. These
data imply that only half the hippocampus is required for consolidation of
passive avoidance memory. This is consistent with other studies showing that
rats subjected to unilateral hippocampal lesions display normal T maze
alternation and only a minor deficiency in the Morris water maze. Similarly,
animals with unilateral lesions of the fimbria fornix are able to learn in a
variety of spatial paradigms including the Morris water maze and the eight arm
radial maze. Since the fimbria fornix provides the major connections of the
hippocampus with subcortical forebrain structures, these lesion studies provide
further evidence for a bilateral functional redundancy in the hippocampal system
(Wong, 1999 and references therein).
Stimulation of adenylyl cyclase in the hippocampus is critical for memory formation. However, generation of cAMP signals within an optimal range for memory may require a balance between stimulatory and inhibitory mechanisms. The role of adenylyl cyclase inhibitory mechanisms for memory has not been addressed. One of the mechanisms for inhibition of adenylyl cyclase is through activation of Gi-coupled receptors, a mechanism that could serve as a constraint on memory formation. Ablation of Gialpha1 by gene disruption increases hippocampal adenylyl cyclase activity and enhances LTP in area CA1. Furthermore, gene ablation of Gialpha1 or antisense oligonucleotide-mediated depletion of Gialpha1 disrupts hippocampus-dependent memory. It is concluded that Gialpha1 provides a critical mechanism for tonic inhibition of adenylyl cyclase activity in the hippocampus. It is hypothesized that loss of Gialpha1 amplifies the responsiveness of CA1 postsynaptic neurons to stimuli that strengthen synaptic efficacy, thereby diminishing synapse-specific plasticity required for new memory formation (Pineda, 2004).
The cAMP and ERK/MAP kinase (MAPK) signal transduction pathways are critical for hippocampus-dependent memory, a process that depends on CREB-mediated transcription. However, the extent of crosstalk between these pathways and the downstream CREB kinase activated during memory formation has not been elucidated. This study reports that PKA, MAPK, and MSK1, a CREB kinase, are coactivated in a subset of hippocampal CA1 pyramidal neurons following contextual fear conditioning. Activation of PKA, MAPK, MSK1, and CREB is absolutely dependent on Ca2+-stimulated adenylyl cyclase activity. It is concluded that adenylyl cyclase activity supports the activation of MAPK, and that MSK1 is the major CREB kinase activated during training for contextual memory (Sindreu, 2007).
One of the major objectives of this study was to identify which MAPK-activated CREB kinase is stimulated during memory formation. Furthermore, it was important to define the relationship between MAPK and cAMP signaling following training for contextual fear conditioning, and to determine why Ca2+-stimulated adenylyl cyclase activity is required for contextual memory. There are several mechanisms by which cAMP could contribute to memory, including regulation of AMPA receptor trafficking and MAPK activation. No increased PKA phosphorylation of AMPA receptors was detected following contextual fear conditioning. Consequently, focus was placed on the role of cAMP signaling in MAPK activation because of the central role played by MAPK during memory formation. Confocal imaging was used to identify individual hippocampal cells in which PKA, MAPK, and CREB kinases are activated after contextual fear conditioning. It has not been previously shown that contextual fear conditioning activates PKA, nor was it known that PKA and MAPK are activated in the same neurons in the hippocampus. Furthermore, there was no evidence for activation of specific CREB kinases following fear conditioning (Sindreu, 2007).
Training for contextual memory caused a 5- to 6-fold increase in MAPK activation in approximately 10% of CA1 pyramidal neurons in two distinct intracellular pools: a nuclear pool and a postsynaptic pool. Furthermore, PKA was activated in the same subset of neurons as MAPK, and both showed increased nuclear activities after training. MAPK activation strongly correlated with activation of MSK1, a CREB kinase. Most importantly, the training-induced increases in MAPK, PKA, and MSK1 activities were ablated in mice lacking Ca2+-stimulated adenylyl cyclase activity. It is concluded that one of the major roles of cAMP signaling in memory is to support the activation and nuclear translocation of MAPK in CA1 pyramidal neurons (Sindreu, 2007).
Signal transduction pathways are usually implicated in memory formation because they are activated in specific areas of the brain by training and inhibition of the pathway blocks memory. For example, MAPK activity is stimulated in area CA1 following training for hippocampus-dependent memory, and administration of MEK inhibitors blocks both training-induced increases in MAPK and memory formation. Ca2+-stimulated adenylyl cyclase and PKA activities are required for memory formation, suggesting that either basal PKA activity is necessary or that an increment in PKA activity contributes to memory. Using an antibody that recognizes phosphorylated PKA substrates (pPKA-s), it was discovered that PKA is not only activated in area CA1 following contextual fear conditioning, but there is also a strong correlation between neurons showing MAPK activation and those in which PKA is activated. In keeping with this, increased nuclear levels of the PKA catalytic α subunit was observed in pERK+ neurons after training. The increase in pPKA-s was readily blocked by inhibitors of PKA and lost in mice lacking Ca2+-stimulated adenylyl cyclase activity, thus validating the use of the pPKA-s antibody to monitor PKA activation (Sindreu, 2007).
The observation that fear conditioning activates MAPK selectively in area CA1 agrees with other evidence that stimulation of transcription in this area of the hippocampus is particularly important for contextual memory formation. Much less was known, however, about the identity and size of the cellular population activated during training for contextual memory, and the intracellular compartments in which MAPK is stimulated. Although this analysis focused on the role of MAPK in the nucleus because of its importance for CREB-mediated transcription, MAPK was simultaneously activated in dendrites and at distal synapses following fear conditioning. It is noteworthy that MAPK regulates a number of other proteins, including dendritic K+ channels and glutamate receptors, and it may also control dendritic protein synthesis. Thus, the parallel activation of synaptodendritic and somatonuclear pools of MAPK supports the general hypothesis that memory formation depends on several MAPK-regulated events, including synaptic activity, dendritic protein synthesis, and transcription (Sindreu, 2007).
Although CREB-mediated transcription is necessary for memory formation and depends on MAPK signaling, the CREB kinase activated by MAPK following training for contextual memory was not certain. It was particularly interesting to determine if training for contextual fear activates RSK2 or MSK1 because studies using cultured neurons have implicated both kinases in CREB-mediated transcription through the phosphorylation of transcription factors and histones. This study discovered that fear conditioning activates MSK1, but not RSK2, in CA1 neurons, and that activation of MAPK and MSK1 is tightly correlated on a cell-by-cell basis. Furthermore, the activation of MSK1 induced by training is abrogated in mice lacking Ca2+-stimulated adenylyl cyclases or by post-training inhibition of MEK1/2. This strongly implicates MSK1 in MAPK-dependent CREB phosphorylation during formation of contextual memory. The identification of MSK1, and not RSK2, as the activated CREB kinase emphasizes that signaling mechanisms inferred from cultured neuron studies do not necessarily apply in vivo. Definitive evidence as to the relative importance of both CREB kinases during memory formation may come from the use of conditional mutant mice or novel MSK1 antagonists (Sindreu, 2007).
In summary, the data indicates that stimulation of MAPK in dendrites and the nucleus following training for contextual memory depends on Ca2+-stimulated adenylyl cyclase activity and leads to the activation of the CREB kinase MSK1. Furthermore, signaling elements for CREB-mediated transcription, starting with the initial cAMP signal, and including PKA, MAPK, MSK1, and CREB, are all activated in the same subset of neurons after training. It is concluded that one of the major roles of adenylyl cyclase activity in memory is to support the activation of MAPK, MSK1, and CREB in hippocampal neurons (Sindreu, 2007).
Mammalian models of longevity are related primarily to caloric restriction and alterations in metabolism. Mice in which type 5 adenylyl cyclase (AC5) is knocked out (AC5 KO) and which are resistant to cardiac stress have increased median lifespan of ~30%. AC5 KO mice are protected from reduced bone density and susceptibility to fractures of aging. Old AC5 KO mice are also protected from aging-induced cardiomyopathy, e.g., hypertrophy, apoptosis, fibrosis, and reduced cardiac function. Using a proteomic-based approach, a significant activation of the Raf/MEK/ERK signaling pathway and upregulation of cell protective molecules, including superoxide dismutase, has been demonstrated. Fibroblasts isolated from AC5 KO mice exhibited ERK-dependent resistance to oxidative stress. These results suggest that AC is a fundamentally important mechanism regulating lifespan and stress resistance (Yan, 2007).
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