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Tully and Bolshakov Molecular Brain 2010, 3:15
http://www.molecularbrain.com/content/3/1/15
Open Access
REVIEW
Emotional enhancement of memory: how
norepinephrine enables synaptic plasticity
Review
Keith Tully* and Vadim Y Bolshakov
Abstract
Changes in synaptic strength are believed to underlie learning and memory. We explore the idea that norepinephrine
is an essential modulator of memory through its ability to regulate synaptic mechanisms. Emotional arousal leads to
activation of the locus coeruleus with the subsequent release of norepineprine in the brain, resulting in the
enhancement of memory. Norepinephrine activates both pre- and post-synaptic adrenergic receptors at central
synapses with different functional outcomes, depending on the expression pattern of these receptors in specific neural
circuitries underlying distinct behavioral processes. We review the evidence for noradrenergic modulation of synaptic
plasticity with consideration of how this may contribute to the mechanisms of learning and memory.
Introduction
Specific cells and synapses within implicated neural circuits are recruited during learning, such that memory
allocation is not random but rather is regulated by precise
mechanisms which define where and how information is
stored within the neural network [1]. Nearly four decades
ago, Seymour Kety suggested that emotionally arousing
experiences may be associated with activation of the
locus coeruleus, sending adrenergic projections to different regions of the brain (such as hippocampus, cortex and
cerebellum) [2]. Moreover, he proposed that activation of
β-adrenoreceptors by released norepinephrine (NE)
could result in facilitation of synaptic transmission
through the mechanism involving increases in the intracellular cAMP concentration and new protein synthesis,
thus contributing to the memory acquisition and maintenance. It is currently hypothesized that synaptic plasticity, specifically long-term potentiation (LTP), in the
neural circuits of learned behaviors could provide a cellular substrate of memory storage [3]. Consistent with
Kety’s proposal, it has been demonstrated recently that
direct activation of the locus coeruleus initiated protein
synthesis-dependent LTP at the perforant path input to
the dentate gyrus in awake rats [4]. At the behavioral
level, there is overwhelming evidence that emotionallycharged events often lead to the creation of vivid long* Correspondence: ktully@mclean.harvard.edu
1
Department of Psychiatry, McLean Hospital, Harvard Medical School, 115 Mill
Street, Belmont, Massachusetts 02478, USA
Full list of author information is available at the end of the article
lasting memories [5,6], in part due to a surge of norepinephrine and subsequent stimulation of adrenergic
receptors in the nervous system [7,8], and, as a result,
improved memory consolidation [6]. Unexpectedly,
recent studies of the human subjects indicate that
although emotionally-charged events are remembered
better than emotionally neutral experiences, emotion
may enhance the subjective sense of recollection more
than memory accuracy [9].
The results of numerous previous experiments implicate the amygdala in acquisition and retention of memory
for emotionally charged events [reviewed in [10-12]].
Thus synaptic enhancements in the conditioned stimulus
(CS) pathways to the lateral nucleus of the amygdala were
shown to contribute in the acquisition of fear memory to
the acoustic CS during auditory fear conditioning [1317]. It has been demonstrated also that the basolateral
amygdala can regulate consolidation of memories in
other regions of the brain [6,18]. The contribution of the
amygdala to modulating memory consolidation critically
depends on activation of β-adrenoreceptors in the BLA
[19-21]. According to the emotional tagging concept,
activation of the amygdala during emotionally arousing
events could mark the experience as important and aid in
enhancing synaptic plasticity in other regions of the brain
[22]. Consistent with this notion, it has been shown previously that the actions of NE in the BLA promote the
induction of LTP [23] and the expression of Arc protein,
implicated in mechanisms of synaptic plasticity and
memory formation, in the hippocampus [24]. On the
© 2010 Tully and Bolshakov; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Com-
BioMed Central mons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Tully and Bolshakov Molecular Brain 2010, 3:15
http://www.molecularbrain.com/content/3/1/15
other hand, plasticity in the auditory thalamus (specifically in the medial division of the medial geniculate
nucleus and posterior intralaminar nucleus), prior to projections to the LA, plays an essential role in auditory fear
conditioning [25,26]. This supports the notion that plasticity in multiple regions of the brain may contribute to
the formation of fear memory [26].
Recent reviews have examined the role of the noradrenergic system in emotional memory [27], the influence of
norepinephrine on fear circuitry [28], and the function of
norepinephrine system in general [29]. Learning to recognize important cues in our environment with emotional
salience, such as danger or altruistic social interactions, is
an essential survival mechanism. Thus evolution has
shaped our nervous system to robustly remember cues
that elicit emotion. While some emotional responses are
hard-wired into the brain’s circuitry, many of them are
learned through experience [10]. How do we remember
emotionally charged events so well, and what does it tell
us about the mechanisms of memory storage in the brain?
Most of our experiences and information detected by our
senses are not remembered. How does our brain know
what events are important enough to be preserved for
long-term storage? One important clue comes from the
fact that the transition of the behavioral experiences into
memory likely arises from changes in the efficiency of
synaptic transmission in corresponding neuronal pathways [30-32,15]. In this review we will consider at the
level of changes in synaptic function how creation of
long-lasting memories during emotional arousal might be
linked to a surge of norepinephrine in specific neural circuits.
Mechanisms of NE production and routes of its
delivery in the brain
Norepinephrine, also called noradrenaline, is a catecholamine produced by dopamine β-hydroxylase [33]
which is released either as a hormone from the adrenal
medulla into the blood or as a neurotransmitter in the
brain. Norepinephrine in the brain is synthesized primarily in neurons in the locus coeruleus and to a lesser extent
in the lateral tegmental field [29]. Within these neurons
norepinephrine is transported by vesicular monoamine
transporters into synaptic vesicles and carried along the
axons composing the noradrenergic bundle to the sites of
release [34] (Figure 1). These neurons send projections
throughout the brain where norepinephrine performs its
action upon release and binding to the G protein-coupled
adrenergic receptors. It is followed by degradation of norepinephrine and/or its reuptake. There are two classes of
adrenergic receptors, α and β, with each of them divided
into several subtypes [35]. The subtypes of α receptors
include Gq-coupled α1receptors and Gi-coupled α2 receptors. Activation of three different subtypes of β-receptors
Page 2 of 9
Adrenergic receptors
A
A

A
G
Gq
Gq
A
A
A
Gi
Gi
B  
B  
Gs
Gs
Post-synaptic
Pre-synaptic
[
Locus
Coeruleus
vesicular monoamine
transporter
ra
ansporter
Norepinephrine
dopamine
B-hydoxylase
B
h d
hydoxylase
l
Dopamine
Figure 1 Norepinephrine is synthesized from dopamine by dopamine β-hydroxylase in neurons of the locus coeruleus. Before the
final β-oxidation, norepinephrine is transported into synaptic vesicles
by a vesicual monoamine transporter. The vesicles are then transported along the axons comprising the noradrenergic bundle to release
sites. At the synapse norepinephrine is released into the synaptic cleft
where it binds to various pre- and post-synaptic adrenergic receptors
which subsequently activate distinct G protein coupled signal cascades.
(β1, β2, β3), linked to Gs proteins, results in a rise in the
intracellular cyclic AMP concentration and subsequent
PKA activation.
The locus coeruleus is a nucleus composed of mostly
medium-size neurons located within the dorsal wall of
the rostral pons in the lateral floor of the fourth ventricle
that serves as the principal site for synthesis of norepinephrine in the brain [36]. The projections of the locus
coeruleus spread throughout the central nervous system,
with heavy innervation of the amygdala, brain stem, spinal cord, cerebellum, hypothalamus, thalamic relay
nuclei, cingulate gyrus, hippocampus, striatum, basal telencephalon, and the cortex [37]. The action of norepinephrine in each neuroanatomical region is determined
by the expression patterns of the various adrenergic
receptor subtypes.
The role of NE in memory
The mechanisms of memory could be best understood
with the systematic application of associative learning
paradigms. Short-term memory is normally defined and
measured by retrieval tests that occur within the first few
Tully and Bolshakov Molecular Brain 2010, 3:15
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hours following the acquisition event, while long-term
memory is typically measured using retrieval tests that
occur at later times, following many hours or even days
after the memory was acquired [3]. Numerous animal
studies repeatedly demonstrated the role of adrenergic
system in consolidation of memory for emotionally significant experiences [reviewed in refs. [6] and [38]]. In
experiments using in vivo microdialysis and high-performance liquid chromatography (HPLC), NE release in the
rat amygdala was detected in response to footshock stimulation which is usually used in inhibitory avoidance
training paradigm [39]. NE levels were increased to
approximately 75% above a basal concentration. Immobilization and tail pinch in rats were also shown to increase
extracellular concentration of norepinephrine in the lateral and basolateral amygdala, as measured by microdialysis [40], leading to activation of adrenoreceptors present
throughout the amygdala complex [41,42]. These findings
were consistent with the notion that NE released by
arousing stimulation could be involved in the functional
regulation of neural circuits in the amygdala. Moreover,
the amount of NE released in the amygdala during inhibitory avoidance training correlated strongly with 24-h
retention performance [43]. Infusions of the β-receptor
antagonist into the amygdala following inhibitory avoidance training resulted in amnesia in rats [44], while intraamygdala injections of β-adrenergic agonists enhanced
memory consolidation [19,45].
The acquisition of conditioned fear memory could also
be modulated by pretraining manipulations of NE concentration in the amygdala [46]. Rats treated systemically
with the GABAA receptor antagonist picrotoxin, used in
the memory-enhancing doses, showed a substantial
increase in levels of NE in the amygdala, while systemic
injections of the memory impairing doses of the GABAA
receptor agonist muscimol resulted in decreased levels of
NE [47,6]. These findings supported the view that drugs
that are capable of modulating emotional memory, such
as GABAergic agonists and antagonists, may do so by
controlling the level of NE within the amygdala [18,47].
Thus animal experiments have generally shown that
injecting norepinephrine to various brain regions at times
when memories are encoded or shortly after the behavioral training could enhance memory performance
[27,48]. Conversely, blocking adrenergic receptors (such
as β-type) could have a decremental effect on memory
[6,49] and prevent the increase of memory performance
during concurrent injections of the agonist [50]. According to a relatively recently proposed hypothesis, memory
reconsolidation could occur when memory is retrieved
and enters the labile state again, requiring additional protein synthesis for its transition into long-term memory
[51,52]. It appears that the process of reconsolidation
could also be modulated through activation of adrenore-
Page 3 of 9
ceptors [53]. Based on cumulative evidence, release of NE
in the amygdala is essential for encoding and retention of
memories for the emotionally significant events.
Surprisingly, genetically-modified mice, in which the
dopamine β-hydroxylase gene was ablated, did not
exhibit any deficits in long-term fear memory following
single-trial fear conditioning [54]. This was an unexpected finding because NE is not produced in these mice.
It might be interesting to determine whether developmental compensations in dopamine β-hydroxylase
knockout mice might be responsible for the lack of
changes in conditioned fear memory in the absence of NE
release during behavioral training. Moreover, postraining
systemic or intra-amygdala administration of the βantagonist propranolol had no effect on consolidation of
fear memory in rats [55]. It is possible, however, that the
concentration of propranolol in this study was too low to
prevent completely activation of β-adrenoreceptor by
endogenous NE, as the ability of amygala-injected propranolol to block consolidation of aversive memories was
previously demonstrated [44].
The human subject studies provided further evidence
that emotional arousal facilitates memory consolidation
in a way that can be blocked by the β-adrenergic receptor
antagonists, e.g. propranolol [6,38,56]. Thus, the blockade of β-adrenoreceptors impairs memory of an emotionally arousing story but does not affect memory of a
closely matched emotionally neutral story [57]. In this
classic study, the subjects who received propranolol
remembered the emotional story no better than a neutral
story. More recently, Segal and Cahill using an adrenergic
biomarker showed that adrenergic activation relates
selectively to memory for emotional events in humans
[58]. One week after viewing a series of mixed emotional
and neutral images a surprise recall test showed endogenous noradrenergic activation immediately after versus
before slide viewing that correlated with the percentage
of emotional pictures recalled. Functional magnetic resonance imaging has shown that encoding of emotional
stimuli increases human amygdala responses, an effect
that is blocked by administration of a β-adrenergic antagonist [59-61]. Interestingly, it has been demonstrated
recently that emotional arousal could enhance the subjective sense of recollection enhancing confidence in the
accuracy of the memory [9]. In these experiments, brain
activity associated with remembering emotional and neutral photos was measured in combination with behavioral
testing. In other words, emotionally arousing events may
boost the feeling of remembering without enhancing the
objective accuracy of memory [62].
By modulating memory for potentially threatening or
harmfulstimuli, norepinephrine may ensure adaptive
behavioral responses when such stimuli are encountered
in the future.
Tully and Bolshakov Molecular Brain 2010, 3:15
http://www.molecularbrain.com/content/3/1/15
NE-mediated regulation of synaptic plasticity in the
amygdala
Recent studies provide evidence that memory of fear
could be acquired and, perhaps, retained through the
mechanisms of LTP in the CS pathways [15,16]. The ability of glutamatergic synapses in fear conditioning circuits
to undergo LTP is tightly controlled by several neuromodulators, such as gastrin-releasing peptide [63], vesicular Zn2+[64], or dopamine [65]. It has been
demonstrated recently that stathmin, a phosphoprotein
enriched in the amygdala and in the auditory CS and US
areas, can control fear memory by regulating the susceptibility of cortico-amygdala and thalamo-amygdala synapses to LTP [66]. Could synaptic plasticity in the circuits
underlying fear conditioning also be modulated by NE? A
persistent late phase of LTP (L-LTP) in cortical and thalamic inputs to the LA, which is induced by repeated high
frequency trains of presynaptic stimulation and is dependent on new protein synthesis, was found to be mediated
by activation of β adrenoreceptors [67]. Conversely, activation of α2-adrenoreceptors impaired the induction of
LTP at projections from the LA to the basal nucleus of the
amygdala [68]. We have recently started exploring synaptic mechanisms by which norepinephrine might modulate plasticity in the CS pathways [69], linked to the
acquisition of conditioned fear memory to auditory stimulation [10,12]. Although we found that norepinephrine
had no direct effect on baseline glutamatergic synaptic
transmission in thalamo-amygdala projections, by which
the auditory CS information is conveyed to the LA from
the auditory thalamus, the number of spikes triggered by
depolarizing current injections in amygdalar neurons was
increased in the presence of norepinephrine. This effect
on neuronal firing properties is consistent with the observation that norepinephrine can inhibit slow after-hyperpolarization that follows trains of action potentials [70]
and hyperpolarization-activated cation currents [71]. To
examine the role of norepinephrine in modulation of synaptic plasticity in thalamo-amygala pathway, we paired
stimulation of thalamic afferents with postsynaptic action
potentials induced in a recorded neuron with a short
delay after the presynaptic stimulus was delivered. This
experimental protocol induced LTP in the presence of the
GABAA receptor antagonist picrotoxin but not when
GABAergic inhibition remained intact. While norepinephrine had no facilitatory effect on LTP induced in the
presence of picrotoxin, the addition of norepinephrine to
the external medium allowed the induction of LTP under
conditions of intact inhibition when it otherwise would
not have occurred. This led us to conclude that norepinephrine may enable the induction of LTP in thalamic
input to the lateral amygdala by suppressing inhibitory
GABAergic neurotransmission.
Page 4 of 9
Consistent with the role of norepinephrine in the regulation of inhibitory drive, it has been found previously
that norepinephrine reduced the frequency of spontaneous inhibitory postsynaptic currents in rat supraoptic
neurons [72]. We further showed that norepinephrine
reduced the frequency of spontaneous inhibitory postsynaptic currents in the LA and reduced the peak amplitude of disynaptic GABAergic inhibitory postsynaptic
currents, strengthening the notion that NE may permit
the induction of LTP by decreasing inhibition of principal
neurons by local circuit interneurons. On the other hand,
activation of α2-adrenoreceptors was shown previously to
result in inhibition of excitatory postsynaptic responses
in inputs to neurons in the basal nucleus, while activation
of β-adrenoreceptors led to the strengthening of glutamatergic neurotransmission at the same synapses [73].
Consistent with these earlier findings, we found that
application of norepinephrine in the presence of the α2
antagonist induced potentiation of thalamo-amygdala
synaptic responses, an effect that was reversed by the βadrenoreceptor antagonist. When norepinephrine was
applied in the presence of the β-adrenoreceptor antagonist, the synaptic response was reduced, an effect that
was partially reduced by the α2 antagonist. Thus, the
oppositely directed effects on synaptic transmission during simultaneous activation of different adrenoreceptor
subtypes are likely to be mutually exclusive under baseline conditions, but may allow for modulation during various behavioral processes in vivo. The ability of NE to
gate LTP at glutamatergic synapses through the NEinduced suppression of GABAergic inhibition could, at
least in part, explain a well-known ability of the GABAergic agonists and antagonist to suppress or promote memory mechanisms, respectively [18].
Modulation of plasticity in the hippocampus
While the amygdala presents us with one of the clearest
examples of how synaptic plasticity in a defined neural
circuitry could control fear-related behavioral responses,
the hippocampus is another important locus of the NE
actions linked to the mechanisms of learning and memory. Using labeled norepinephrine, it was directly demonstrated that NE could be released in the hippocampus in
an activity-dependent fashion. Thus, NMDA application
was shown to induce the release of [3H] norepinephrine
preaccumulated in slices from the hippocampus in both
the dentate gyrus and the CA1 region [74]. A recent study
has shown that norepinephrine-driven phosphorylation
of GluR1 subunit may facilitate AMPA receptor trafficking to synaptic sites and LTP induction in the hippocampus [75]. The results of this work suggested that elevation
of norepinephrine concentration during emotional
arousal could lead to phosphorylation of GluR1, lowering
Tully and Bolshakov Molecular Brain 2010, 3:15
http://www.molecularbrain.com/content/3/1/15
the threshold for the experience-driven synaptic modifications and facilitating the formation of memories. Specifically, norepinephrine application resulted in
phosphorylation of the GluR1 sites Ser845 and Ser831
which facilitated the synaptic delivery of GluR1 in CA1
neurons in the hippocampus. Moreover, norepinephrine
could enhance contextual fear memory formation and
LTP in wild-type mice but not in mice carrying mutations
in the GluR1 phosphorylation sites. Norepinephrine
application induced LTP when paired with a mild electrical stimulation, but not when it was applied alone. This
indicates that synapses would undergo potentiation only
if they are activated within a limited time window of
emotional arousal associated with the surge of norepinephrine in the brain.
This recent study builds on an existing literature supporting a role of norepinephrine in the functioning of
hippocampal circuitry. Thus, it was reported previously
that norepinephrine could induce long lasting modifications of synaptic responses in the dentate gyrus in rats,
associated with differential actions on distinct projections (medial vs. lateral perforant paths) arising in the
entorhinal cortex [76]. The finding, that adrenergic
antagonists could block amphetamine-induced increases
in the dentate gyrus population spike in anesthetized rats
and that an adrenergic agonist enhanced responses to
NMDA, led to the conclusion that adrenergic receptors
enhance reactivity of hippocampal cells to afferent stimulation [77]. It has been reported also that norepinephrine
regulates synaptic plasticity in the CA1 area of young rats
[78], causing a shift in the frequency-response relationship for long-term depression (LTD) induced with the
low frequency theta-burst stimulation and LTP (observed
at higher frequencies), in the β-adrenoreceptor-dependent fashion. Norepinephrine caused a shift toward
potentiation, with the effect of norepinephrine being
most prominent at intermediate frequencies, which
induced no changes in control slices but strong LTP in the
presence of norepinephrine. It has been found later that
an administration of norepinephrine in the CA1 region in
hippocampal slices prepared from more mature animals
allowed for more robust LTP under the conditions when
reduced LTP was normally observed [79]. The effects of
norepinephrine were mimicked by the α1-adrenoreceptor
agonist and were blocked by the α1-adrenoreceptor
antagonist, leading to the conclusion that the actions of
norepinephrine may shift during development. Activation of noradrenergic systems during emotional arousal
may enhance memory formation by inhibiting protein
phosphatases that normally oppose the induction of LTP,
because protein phosphatase inhibitors mimicked the
effects of β-adrenoreceptor activation that enabled the
induction of LTP during long trains of stimulation at CA1
synapses [80]. In the experiments on 6-hydroxydop-
Page 5 of 9
amine-treated rats, lacking norepinephrine, it was shown
that LTP but not LTD was blocked at CA1 synapses,
while application of norepinephrine restored LTP and
blocked LTD [81]. This plasticity occurred through activation of β-adrenoreceptors and involved the cAMP/PKA
pathway. Importantly, several studies directly demonstrated that activation of locus coeruleus neurons produces adrenoreceptor-mediated LTP-like synaptic
enhancements in the dentate gyrus [4,82-84]. The release
of NE in the hippocampus during emotionally-charged
events could thus modulate the hippocampus-dependent
forms of memory by controlling the induction of synaptic
plasticity at corresponding synapses in hippocampal neuronal circuits.
The role of second messengers in regulation of
synaptic plasticity by NE
The better understanding of the mechanisms by which
emotional arousal could enhance the brain’s ability to
store, retain, and subsequently recall information, would
require a detailed characterization of the signaling pathways lying downstream of norepinephrine binding to
adrenergic receptors. Norepinephrine activates various
subtypes of adrenergic receptors, so it is not surprising
that evidence is accumulating for the differential roles of
signaling pathways tied to distinct receptor classes in synaptic plasticity. Thus, the extracellular signal-regulated
MAP kinase (ERK) is activated by β-adrenoreceptors in
somas and dendrites of CA1 pyramidal neurons in a
PKA-dependent fashion [85]. It plays a regulatory role in
the induction of certain forms of LTP at the Schaffer collateral-CA1 synapses. ERK was found to be required for
the early phase of LTP elicited by brief presynaptic stimulation, as well as for LTP elicited by prolonged stimulation paired with β-adrenoreceptor activation in CA1
pyramidal neurons. In a later study, coactivation of βadrenoreceptors and cholinoreceptors was found to
enhance LTP at CA1 synapses through convergent, synergistic activation of mitogen-activated protein kinase
[86]. In another work, synaptic stimulation, which was
subthreshold for the induction of late phase LTP (L-LTP),
triggered this form of plasticity when LTP-inducing stimulation was delivered in the presence of the β-adrenoreceptor agonist [87]. The induction of this form of LTP
also required activation of ERK. Further research is
clearly needed to decipher the signaling cascades initiated by the binding of norepinephrine to adrenergic
receptors linked to the various G proteins, mediating
activation of the specific signal transduction pathways
and implicating either adenylyl-cyclase (through Gi-coupled α2 receptors and Gs-coupled β1, β2, and β3 receptors) or phospholipase C (through Gq-coupled
α1receptors). This knowledge would result in under-
Tully and Bolshakov Molecular Brain 2010, 3:15
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standing of how second messengers may interact with the
mechanisms of synaptic plasticity in the brain in the context of specific forms of learning and memory.
The effects of NE in other neural circuits
As the noradrenergic bundle sends projections throughout the central nervous system, it is expected that norepinephrine would modulate synaptic plasticity in other
neural circuits besides the hippocampus and amygdala.
Consistent with this prediction, it has been demonstrated
recently that activation of α2 adrenoreceptors by NE in
Purkinje cells could control short-term and long-term
associative plasticity at the parallel fiber synapses [88]. In
the cerebellar circuitry, norepinephrine was affecting
synaptic plasticity by decreasing the probability of release
at the climbing fiber synapse, which in turn decreased the
climbing fiber-evoked dendritic calcium signals. In addition, this study demonstrated that norepinephrine was
acting presynaptically to decrease the probability of neurotransmitter release at climbing fibers but not at granule
cell parallel fibers. The reduction in dendritic calcium
elevation, associated with complex spikes, was independent of postsynaptic G protein signaling. Moreover, activation of α2-receptors interfered selectively with the
induction of associative synaptic plasticity. Thus, noradrenergic modulation in this system could provide a
mechanism for context-dependent modulation of associative plasticity and memory. In slices of the rat visual
cortex, paired-pulse stimulation in the presence of NE
resulted in a form of homosynaptic LTD [89]. This noradrenergic facilitation of LTD was blocked by the α1 receptor antagonist and mimicked by the α1 agonist. In the
developing visual cortex in rats, LTP at inhibitory synapses could be induced by the high frequency stimulation
when excitatory neurotransmission was blocked [90].
The induction of this form of LTP, mediated by presynaptic calcium entry, was facilitated by norepinephrine.
In several brain circuits, α2-adrenoreceptor-dependent
inhibition of excitatory glutamatergic signaling was
observed. Norepinephrine, acting at presynaptic α2
receptors, inhibited single fiber glutamatergic inputs
from the nociceptive pontine parabrachial nucleus to the
central amygdala [91]. This effect of NE, mediated by
decreases in the number of active release sites, could
potentially explain how norepinephrine can decrease
pain sensation under stress. Activation of presynaptic α2adrenoreceptors on inputs to sympathetic preganglionic
neurons in slices of neonatal rat spinal cord also
decreased glutamate release [92]. In these experiments,
norepinephrine produced dose-dependent and reversible
decreases in the amplitude of the excitatory postsynaptic
response. Interestingly, the previous experiments, using a
microdialysis technique to estimate the extracellular lev-
Page 6 of 9
els of norepinephrine and glutamate in the bed nucleus of
the stria terminalis in rats, demonstrated that norepinephrine could exert α2-dependent inhibition over both
its own and glutamate release [93]. At the calyx of Held
synapses, NE was shown to increase the high frequency
firing. This was associated with the initial suppression of
glutamatergic excitatory postsynaptic currents through
α2-dependent inhibition of calcium influx [94].
Taken together, these findings indicate, that while NE
can produce a variety of the effects on synaptic and neuronal mechanisms in different regions of the brain, the
expression patterns of different NE receptor subtypes in
specific neural circuits could determine the resulting
functional outcome.
Modulation of GABAergic transmission by NE
Presently, there is substantial evidence that activation of
adrenoreceptors by norepinephrine can modulate
GABAergic inhibitory systems in the brain. Thus, activation of the locus coeruleus resulted in suppression of
feedforward interneurons in rat dentate gyrus, thereby
promoting conditions for the induction of synaptic plasticity [95]. In the LA, NE was inducing hyperpolarizing
currents in local circuit interneurons leading to their
decreased excitability, and, therefore, to decreased feedforward inhibition of principal neurons [69]. This facilitated the induction of LTP at thalamo-amygdala
synapses. Additionally, there are multiple reports suggesting that norepinephrine could, in fact, enhance inhibition. Thus, NE excited medial septum and diagonal
band of Broca GABAergic neurons [96]. NE was shown
also to increase the frequency and the amplitude of
GABAergic inhibitory postsynaptic currents in substantia gelatinosa [97]. In CA1 pyramidal neurons, norepinephrine
increased
action
potential-dependent
inhibitory postsynaptic currents by depolarizing surrounding inhibitory interneurons [98]. It was reported
also that NE can potentiate the Purkinje cell responses to
GABA due to triggering the signaling cascade involving
Gs-linked β-adrenoreceptors activating the cAMPdependent pathway [99]. In the hypothalamic paraventricular nucleus, NE was shown to increase the frequency
of spontaneous inhibitory synaptic current via postsynaptic α1-adrenoreceptors and decrease it through activation of α2-adrenoreceptors on GABAergic terminals
[100]. As the susceptibility of central synapses to LTP is
determined by the strength of GABAergic inhibition, NE
can contribute to the behaviorally-induced plasticity in
the brain through its ability to modulate inhibitory inputs
to projection neurons.
Tully and Bolshakov Molecular Brain 2010, 3:15
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Conclusions
It is well established that emotional arousal modulates the
formation of memory, and a substantial literature, of
which only a fraction is cited in this review, points to a
critical role for the release of norepinephrine in such
modulation. The electrophysiological studies have begun
to elucidate how norepinephrine could modulate both
synaptic transmission and plasticity in specific neural circuits. Storing memories in the brain likely requires
changes in the number, structure, and function of synapses [3]. Considerable progress has been made in relating the activity-dependent changes in synaptic strength
to the mechanisms of learning and memory [101]. It
appears that the mechanisms by which the release of norepinephrine during emotional arousal affects memories
most likely involve modulation of synaptic plasticity in
corresponding neural circuits. As investigative technologies, allowing manipulating the expression of specific
proteins through genetic or epigenetic means, or techniques for delivery of pharmacological agents to the specific sites in the brain mature over the coming decade, the
promise of therapeutic strategies for the treatment of a
host of mental illnesses may be realized. It is critical that,
in parallel, we understand in detail the mechanisms by
which norepinephrine may alter memory processing
through its interactions with the various pre- and postsynaptic adrenoreceptors in specific neural circuits.
Page 7 of 9
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
Abbreviations
AMPA: α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate; cAMP: Cyclic
adenosine monophosphate; ERK: extracellular signal-regulated kinase;GABA: γaminobutyric acid; GluR1: AMPA receptor subunit; LTP: long-term potentiation;
LTD: long-term depression; MAPK: mitogen-activated protein kinase; NMDA: Nmethyl-D-aspartic acid; PKA: cAMP-dependent protein kinase
20.
21.
Competing interests
The authors declare that they have no competing interests.
22.
Authors’ contributions
K.T. and V.Y.B. wrote, read and approved the final manuscript
23.
Acknowledgements
This work was supported by the National Institutes of Health Grants.
24.
Author Details
Department of Psychiatry, McLean Hospital, Harvard Medical School, 115 Mill
Street, Belmont, Massachusetts 02478, USA
25.
Received: 23 November 2009 Accepted: 13 May 2010
Published: 13 May 2010
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doi: 10.1186/1756-6606-3-15
Cite this article as: Tully and Bolshakov, Emotional enhancement of memory: how norepinephrine enables synaptic plasticity Molecular Brain 2010,
3:15
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