VIAGRA FOR YOUR SYNAPSES: ENHANCEMENT OF HIPPOCAMPAL LONG-TERM POTENTIATION BY ACTIVATION OF BETA-ADRENERGIC RECEPTORS

1. Introduction

A major goal of neuroscience research is to determine how enduring memories are made. Such knowledge would enhance therapies for memory disorders and illuminate many key brain functions that rely on enduring memories. Activity-induced changes in synaptic strength (“synaptic plasticity”) are widely believed to underlie memory storage at the cellular level [1,2]. Research has established the principle that synaptic plasticity is critical for associative learning and long-term memory [3,4]. In the mammalian hippocampus, a brain structure critical for making new memories, one form of synaptic plasticity, called “long-term potentiation” (LTP) [5], has been linked to spatial and contextual learning and memory [1,6]. LTP is an activity-dependent increase in excitatory synaptic strength that can last for several hours in isolated brain slice preparations and up to a year in intact animals [7,8]. Many key signaling requirements for LTP (e.g. NMDA receptors, protein kinase-A, calcium-dependent protein kinases) mirror those needed for memory storage in the mammalian brain [6,9-15] . Many manipulations that modify LTP also alter memory expression. Importantly, LTP-like changes in synaptic efficacy can occur in behaving animals as they learn [4]. Since its discovery by Tim Bliss and Terje Lomo [5], LTP has become the leading candidate synaptic mechanism for memory storage in the mammalian brain.

Many neuromodulatory transmitters control the endurance of LTP and memory. One neuromodulator that can significantly enhance hippocampal LTP stability is noradrenaline (NA). NA fibres originate mainly in the locus coeruleus (LC) [16]. LC projects widely throughout the forebrain, providing dense innervation to the hippocampus, amygdala, and thalamus [16]. As such, NA can influence many key brain functions such as attention, arousal, sleep, learning, and memory. The hippocampus is richly innervated by noradrenergic fibres from the LC, and endogenous release of NA can induce persistent synaptic plasticity [17,18]. Interestingly, hippocampus-dependent memory is impaired following reduction of NA or after blockade of β-ARs [19,20]. In the hippocampus, NA binds to β-ARs to enhance the endurance of LTP and promote stability of memories. However, the signaling mechanisms that enable β-ARs to enhance the longevity of LTP are unclear. Because LTP has been strongly correlated with memory storage, understanding how β-ARs modulate the persistence of LTP will shed light on how these receptors regulate memory storage. In this review, we highlight several signaling mechanisms believed to enable β-ARs to enhance the expression of long-lasting forms of hippocampal LTP. We focus on hippocampal β-ARs because of the important roles of these receptors in enhancing LTP and memory. α-ARs are not covered here; their roles in hippocampal synaptic plasticity and memory storage are reviewed elsewhere [21].

2. β-AR Signaling: Importance for Synaptic Plasticity in the Mammalian Hippocampus

NA binds to noradrenergic receptors coupled to G-proteins that initiate intracellular signaling. These can be broadly classified as α1-, α2-, β1-, and β2-ARs [21]. In the hippocampus, all four of these receptor subtypes are expressed in pyramidal neurons and dentate granule cells [22,23]. β-ARs are also expressed outside of the hippocampus, mainly in the cortex, thalamus, and cerebellum [22,24]. Interneurons apparently express very few or no β-ARs [22,23], and glia in area CA1 express mainly β2-ARs [25]. Both β1- and β2-ARs are strongly activated by the noradrenergic agonist, isoproterenol [16]. Stimulation of β-ARs, either with isoproterenol or NA, generally increases intracellular cAMP through G_s-mediated activation of adenylyl cyclase [26].

It has been shown that β-ARs importantly modulate numerous processes involved in synaptic plasticity through cAMP-mediated activation of cAMP-dependent protein kinase (PKA) [29]. cAMP-dependent activation of PKA also recruits other key signaling pathways in hippocampal cells, including the extracellular signal-regulated protein kinase (ERK) pathway via Rap1 (a GTPase) and B-Raf (a protein kinase) [30]. Specifically, Rap1 is involved in cAMP-dependent ERK activation by β2-ARs [30].

Other more recently discovered mechanisms may diversify signaling targets downstream of β-ARs. Interestingly, studies of non-neuronal cells have revealed that, under certain conditions, β2- [27] and β1-ARs [28] may switch their signaling mode from Gs to G_i. This switch appears to be mediated by Gβγ subunits, Src, Ras, and c-Raf1 [31]. It also requires previous phosphorylation of the β-AR by PKA, suggesting that desensitization of the receptor to Gs-dependent signaling may enable Gi signaling. β-AR-dependent Gi signaling in cell lines and in vivo can activate ERK [32-34]. Furthermore, the signaling mode of β-ARs is dynamically regulated, as recruitment of specific phosphodiesterases to the β-AR signaling complex can decrease receptor phosphorylation and subsequently prevent further signaling through the Gi pathway [35]. It is unclear whether such switching can occur in hippocampal neurons, and if so, how it might impact synaptic plasticity.

3. Regulatory control of β-AR signalling

Intracellular signaling events engaged by β-AR activation have several regulatory feedback mechanisms that serve to both prevent activation of downstream effectors in the absence of β-AR agonists and amplify β-AR-dependent responses by compartmentalizing second messenger signalling [36]. Phosphodiesterases (PDEs) are the primary enzymes for cAMP degradation and can constrain β-AR -dependent cellular responses. The primary PDE isoform in the CNS is PDE4 and regulation of β-AR desensitization is mediated through various PDE4 isoforms, which in turn are regulated through phosphorylation by kinases including PKA and ERK [36,37]. PKA phosphorylates PDE4, which hydrolyzes cAMP, thereby restricting cAMP activity in a negative feedback mechanism [36,37]]. However, particular PDE4 isoforms mediate their effects through the presence of particular regulatory domains known as upstream conserved regions (UCRs) which contain PKA and ERK binding sites [36]. Long isoforms of PDE4 contain both UCR1 and UCR2 . UCR1 contains a PKA binding site which allows for the activation of PDE4 in the presence of PKA and subsequent downregulation of cAMP [36]. Conversely, ERK binding to the UCR1 inhibits PDE4 thereby preventing PDE4-dependent β-AR desensitization. ERK activates and has no effect respectively, on the so-called short (lacks UCR1, contains UCR2) and super-short (lacks UCR1, truncated UCR2) PDE4 isoforms [36,37]. Thus, activation of β-AR s and subsequent induction of PKA and ERK can both facilitate and limit cellular responses depending on the presence of specific PDE4 isoforms which play dynamic regulatory roles in β-AR -dependent signaling cascades.

As excessive cAMP signaling may contribute to the pathogenesis of several disease states, PDE inhibitors are potentially useful therapeutic agents for the treatment of conditions such as cancer, inflammatory (asthma, chronic obstructive pulmonary disease, arthritis) diseases, depression and neurodegenerative disorders [36-39]. Interestingly, increased expression of PDE4 has been observed following chronic administration of antidepressants, with the high-affinity conformer involved in the effects of antidepressants that target the NA and 5-HT systems [38]. Furthermore, sleep deprivation, which has been implicated in the pathogenesis of depression and cognitive dysfunction, increases the activity of PDE4, which correlates with impaired cAMP- and PKA-dependent synaptic plasticity and memory formation in sleep-deprived mice[40]. These results suggest that cellular mechanisms required for normal cognitive function and synaptic plasticity are influenced by PDE4 activity and that PDEs may regulate information processing in the CNS.

Inhibition of PDEs enhances LTP, learning and memory processes [40-42]. Application of rolipram, a selective inhibitor of PDE4, to hippocampal slices facilitates the induction of late-LTP by subthreshold stimulation paired with forskolin activation [43]. Rolipram also facilitates heterosynaptic long-term depression [41]. Additionally, synaptic plasticity and context-specific memory can be restored by rolipram treatment following sleep deprivation [40], and long-term contextual memory formation is improved in mice if rolipram is administered prior to training in a hippocampus-dependent task [43]. Results from animal models and preclinical studies indicate that Alzheimer's disease symptoms, such as dementia and memory loss , can be alleviated by PDE inhibitor treatments [39].

β-arrestin, a multifunctional adapter protein, can also initiate intracellular signaling events downstream of the β-AR in a G-protein-independent manner [44,45]. Although β-arrestin mediates termination of G-protein dependent receptor signaling by physically uncoupling the receptor from G-proteins, it generates a second wave of signaling that has a distinct temporal profile and subcellular downstream targets compared to the original receptor response [44,46]. In HEK cell culture, stimulation of β1-ARs initiates β-arrestin-dependent signaling and consequent sustained ERK activation that is restricted to the cytosol [45]. This subcellular targeting may be mediated by ubiquitination of β-arrestin, which leads to rapid internalization of β-ARs and formation of a signaling complex (‘signalosome’) [47]. As such, diverse signaling mechanisms can be recruited downstream of β-ARs, and the specifics of these interactions are still being elucidated. The role of such signaling mechanisms in hippocampal neurons is unknown, but it is likely that similar mechanisms exist in neurons to facilitate compartmentalization and temporal restriction of signaling.

PDEs interact with membrane-bound scaffolding proteins such as β-arrestin, AKAPs and RACK1, which can compete for access to PDE4 isoforms, thus modulating β-AR signaling [36,48]. Importantly, PDEs can interact with β-arrestin in a β-AR -subtype specific manner [49,50]. In cardiomyocytes, inactive β 1ARs complex directly with PDE4D8 which dissociates in the presence of β-AR agonists, whereas stimulation of β2ARs recruits a β-arrestin-PDE45 complex to the β2AR [49]. Sequestering this complex prevents β2ARs from switching to Gi signaling, thereby preventing β2AR desensitization [35,50]. Furthermore, β -arrestin is necessary for recruiting PDE4D5, as selective knockdown of β -arrestin in HEK cells diminishes PDE4D5 sequestration thereby enhancing β -AR desensitization [35]. The ability of β -arrestin to influence receptor conformation and G protein interactions provides potential targets for therapeutic intervention.

Dysfunction of the dopaminergic (DA) system is involved in the pathogenesis of schizophrenia. Several antipsychotics have been found to mediate their effects through β-arrestin-2 which regulates DA signal transduction [51]. Recent evidence suggests that the D2R agonist quinpirole may act by blocking D2R-β-arrestin-2 interactions, thus facilitating Gi/o coupling [52]. β-arrestin-2 also plays a role in another DA-linked pathology, drug addiction. β-arrestin-2 knock-out mice displayed increased striatal extracellular DA release in response morphine administration, which correlated with enhanced conditioned place preference, indicative of enhanced reward experience[42]. These results suggest that β -arrestins provide another mechanism in the regulation of GPCRs which can significantly impact cellular responses and behavioural output by modulating intracellular signaling.

Despite the multitude of signaling mechanisms potentially activated by β-ARs, PKA and ERK are frequently identified as key downstream signaling kinases. PKA and ERK are critical for establishing enduring memories and long-term synaptic plasticity in numerous species, including mammals [3,29,53]. The coupling of β-ARs to these critical signaling pathways may explain the enhancing effects of NA on hippocampal synaptic plasticity and memory. In contrast, α-ARs mediate the inhibitory effects of NA on hippocampal neurons; activation of α-ARs has mixed effects on memory [21]. Thus, to understand how NA enhances synaptic plasticity and memory storage, attention must be primarily paid to β-ARs.

4. Modulation of Excitability by Hippocampal β-ARs

Neuromodulators can affect neuronal ability to undergo synaptic plasticity by changing cellular excitability. Activation of β-ARs generally increases the excitability of principal neurons in the dentate gyrus, area CA3, and area CA1 of the rodent hippocampus. In the dentate gyrus, application of either NA or a β-adrenergic agonist such as isoproterenol induces pathway-specific changes in cellular excitability. β-AR-mediated enhancement of the population spike is observed in the medial perforant path, whereas β-AR-mediated depression is seen in the lateral perforant path [54]. These pathways are histochemically and anatomically distinct, suggesting that differential effects of NA in this subregion may be important for selective information processing [54,55]. β1-ARs also enhance potentiation of the pyramidal cell population spike in areas CA3 and CA1 [56-59]. This increased cellular excitability amplifies the frequency of spontaneous firing in area CA3 [59], potentially facilitating the auto-associative properties of this hippocampal subregion [60].

5. β-AR Modulation of Hippocampal LTP

Highly significant events are easily remembered, often for an entire lifetime. There is evidence to suggest that the physiologic mechanism underlying this retention is related to activation of the brain's noradrenergic system, which promotes plasticity in brain structures that mediate enduring behavioral adaptations[61,62]. A plausible cellular mechanism for enhancement of hippocampal memory by β-ARs is facilitation of enduring LTP by β-ARs. This phenomenon can be studied in vitro by inducing LTP in the presence of β-AR agonists. Long-lasting forms of LTP are induced in hippocampal slices by repeated high-frequency stimulation (HFS, usually 3-4 100-Hz trains), they can last 6-12 hrs, and require translation (protein synthesis) for their stability [3,29,63]. Shorter-lasting LTP is commonly induced by weaker HFS (usually one 100-Hz train), lasts about 2 hrs, and does not require translation [3]. The effect of β-AR activation on LTP is different depending on the hippocampal subregion examined.

6. PKA-Independent β-AR Signalling

Traditionally, cAMP-dependent signaling in hippocampal neurons has been thought to be mediated primarily through PKA (for review, see 29). However, novel cAMP receptors (Epac 1 and 2) also participate in neuronal cAMP-dependent signaling. Epac-dependent, PKA-independent modulation of cellular processes has been demonstrated at the crayfish neuromuscular junction [129], the calyx of Held [130], and in cortical neurons [131]. In the hippocampus, Epac contributes to the forskolin response in cell culture [132], and plays a role in both long-term potentiation [90] and long-term depression [133]. Given the emerging role of Epac as a neuronal signaling molecule that operates alongside PKA to generate a multitude of cAMP-dependent cellular effects, it is possible that β-AR signaling also recruits the Epac pathway.

Indeed, Epac signaling is required for hippocampus-dependent memory retrieval, a process that also requires β1-AR signaling [134,135]. In parallel with the enhancement of long-term memory observed following application of noradrenaline to rodent hippocampus [136], Epac has been found to facilitate long-term memory formation [137]. The details of how the Epac and PKA signaling pathways may interact to generate β-AR-dependent effects on synaptic plasticity and memory remain to be elucidated.

7. Roles of Translational Regulation in β-AR Modulation of LTP

The inhibitory effects of translation inhibitors on LTP can be detected as early as 20 minutes after induction [137-139]. Thus, plasticity-related proteins can be produced rapidly and locally in dendrites after electrical stimulation. Indeed, dendritic expression of some proteins is increased within 5 min. after LTP induction [138]. LTP induced by pairing isoproterenol with one 100-Hz train of HFS (“β-LTP”) requires dendritic translation, but not transcription [84]. Other forms of translation-dependent LTP can be induced by application of brain-derived neurotrophic factor (BDNF), neurotrophin-3, or dopamine to hippocampal slices [140]. Also, pharmacological activation of group-1 metabotropic glutamate receptors (mGluRs) in area CA1 induces translation-dependent long-term depression (LTD) [141]. Thus, activation of multiple receptors, including β-ARs, can induce translation-dependent, long-lasting synaptic plasticity. Because such plasticity may underlie the formation of enduring memories, elucidating how transmitter receptors are coupled to translation is critical for grasping the molecular bases of long-lasting synaptic plasticity and long-term memory.

Cells respond to external stimuli by regulating the translational efficiencies of specific mRNAs. Translation initiation is rate-limiting, and most translational control mechanisms act on initiation [142]. These mechanisms predominantly involve the phosphorylation of eukaryotic initiation factors (eIFs) that help assemble initiation complexes to promote ribosomal binding to mRNAs, a required step for translation initiation [142]. Phosphorylation of many eIFs correlates positively with translation initiation; levels of expression of specific phospho-eIFs are used as measures of translation initiation [142].

One key rate-limiting step during translation initiation for most species of mRNA is formation of the eIF4F initiation complex, which consists of the translation initiation factors eIF4A, 4E, and 4G [142]. The eIF4F complex facilitates binding of the 5’ mRNA cap structure to the ribosome to initiate translation. Formation of the eIF4F complex is possible when 4E is released from its basal state of sequestration by the inhibitory binding protein, 4EBP, and couples with 4G (Fig. 1). Release of eIF4E occurs when 4EBP is phosphorylated by upstream signaling kinases. When 4E is bound to 4G, it can then be phosphorylated by Mnk1 to further upregulate translation initiation. The physiologic significance of this translational control mechanism has been demonstrated by genetic deletion of the predominant neuronal 4EBP isoform (4EBP2) in a mouse model. These mice display increased 4F complex formation in the basal state, and electrical stimuli that generated short-lasting, translation-independent LTP in wildtypes instead induced long-lasting, translation-dependent LTP in the 4EBP2 knockouts [143]. However, a stimulation protocol that generated enduring LTP in wildtype mice failed to elicit long-lasting LTP in 4EBP2 knockout mice. These alterations in synaptic plasticity were paralleled by behavioural observations that 4EBP2 knockout mice have intact short-term, but impaired long-term, memory for hippocampus-dependent memory tasks [143]. Thus, translational control at the level of eIF4F complex formation significantly affects both synaptic plasticity and memory.

Interestingly, β-LTP involves translational upregulation at the level of the eIF4F complex. Increased levels of 4E, 4EBP and Mnk1 phosphorylation are observed when β-LTP is induced, and manipulations that blocked these specific phosphorylations reduced the persistence of β-LTP [144]. 4F complex formation (measured as 4E-4G binding) was also increased during β-LTP [144]. Increased levels of phosphorylated 4EBP were evident in CA1 pyramidal cell dendrites during β-LTP [144], consistent with a dendritic localization of translational control, which may permit rapid, synapse-specific induction of enduring plasticity. HFS-induced LTP and mGluR-LTD involve enhanced 4EBP phosphorylation as well [140], suggesting that increased translation initiation may allow numerous signaling pathways to induce and modulate persistent synaptic plasticity. HFS-induced LTP is associated with ERK-dependent increases in translational capacity [145], evident as increased expression of components of the translational machinery. It is unclear whether β-LTP similarly increases translational capacity.

The roles of signaling pathways involved in translational control in hippocampal neurons are just beginning to be defined [146,147]. Two key signaling kinases involved in translation initiation via the eIF4F complex have been found to have physiologic significance in the hippocampus – mTOR and ERK (Fig. 1). Activation of the mTOR pathway results in phosphorylation of 4EBP, promoting formation of the 4F initiation complex [148]. The ERK pathway similarly facilitates translation by activating Mnk1, a kinase that phosphorylates 4E once it is bound to 4G. Because ERK-dependent 4E phosphorylation occurs when 4E is released from 4EBP, a process that requires mTOR, these two signaling cascades independently converge at regulation of 4E. Both β-LTP and mGluR-LTD require concomitant ERK and mTOR signaling for upregulation of translation initiation and expression of synaptic plasticity. Recruitment of mTOR and ERK signaling pathways may therefore facilitate precise regulation of translation-dependent synaptic plasticity downstream of various neuromodulatory receptors.

In summary, multiple forms of long-lasting synaptic plasticity, including β-LTP, are associated with regulation of a critical translation factor, eIF4E, by ERK and mTOR. Because similar cascades are also activated during long-term plasticity in the marine snail Aplysia [149,150], these pathways may represent evolutionarily conserved mechanisms for translational control of enduring forms of synaptic plasticity.

8. Prospects for Future Research: Signaling Complexes and Glutamate Receptors

An important principle in intracellular signaling is the key role played by adaptor or scaffolding proteins that couple protein kinases and other signaling molecules near their upstream activators and downstream targets, thereby forming signaling complexes that enable fast, efficient, and highly localized signaling. A prominent family of scaffolding proteins that serves this function for the cAMP/PKA signaling pathway are the A-kinase anchoring proteins (AKAPs), a family of more than 50 proteins that contain a binding domain for the type-II regulatory subunits of PKA as well as protein binding domains that couple PKA-bound AKAPs to different target proteins [151].

One AKAP, known as AKAP79/150, not only binds PKA but also contains binding sites for protein kinase C and the Ca²⁺-activated protein phosphatase, calcineurin (PP2B), and is now known to have a crucial role in cAMP/PKA signaling at excitatory synapses in the hippocampal CA1 region. AKAP79/150 is localized at excitatory synapses through interactions with the membrane-associated guanylate kinases (MAGUKs) PSD-95 and SAP97 [152], scaffolding proteins that bind to NMDA and AMPA type glutamate receptors, respectively (Fig. 2) [153]. A number of studies using different manipulations to disrupt this AKAP signaling complex have found significant effects on both synaptic transmission and synaptic plasticity that highlight the important role of AKAPs in cAMP signaling at excitatory synapses. For example, disrupting PKA binding to AKAPs with a peptide that blocks RII binding to AKAPs (Ht31 peptide) induces a rundown of AMPA receptor-mediated currents [154,155] and reduces the numbers of AMPA receptors at the cell surface [156]. Moreover, infusion of the Ht31 peptide into postsynaptic CA1 pyramidal cells leads to a depression of excitatory synaptic transmission in CA1 pyramidal cells that “occludes” the induction of LTD by synaptic stimulation [156]. This suggests that disrupting the association of PKA with AKAP79/150 induces a depression of synaptic strength that shares properties with LTD. Indeed, recent studies indicate that AKAP/PSD-95 interactions are crucial for the induction of LTD, most likely because of the ability of AKAP79/150 and PSD-95 to couple synaptic NMDA receptors to PP2B [157]. Although many of these examples highlight the functional significance of AKAP-mediated association of PP2B with NMDA receptors in regulating AMPA receptor function, PKA-dependent forms of LTP are strongly disrupted in AKAP150 mutant mice, as are forskolin-induced increases in GluR1 phosphorylation at S845 [158]. This indicates that AKAP79/150 has a crucial role in cAMP/PKA signaling at excitatory synapses.

Are AKAPs equally important for β-AR modulation of LTP? β1-ARs are highly localized at excitatory synapses in the hippocampal CA1 region [22,23,25] and yeast two-hybrid screens have shown that the c-terminus of β1-ARs can bind to one of the three PDZ domains in PSD-95 [159]. This suggests that at excitatory synapses, β1-ARs may exist as part of a larger signaling complex containing PSD-95, NMDA receptors, AKAPs, and associated signaling molecules (Fig. 2). In addition, it also appears likely that β1-ARs can form signaling complexes with AMPA receptors, AKAPs, and PKA, mediated by the MAGUK, SAP97 [160]. PSD-95 can also bind to β2-ARs and, via interactions mediated by the transmembrane AMPA receptor regulatory proteins (TARPs), couple these β-ARs to synaptic AMPA receptors [161]. Although the potential role of these signaling complexes in β-AR modulation of LTP has not yet been investigated, recent findings suggest that they have a crucial role in the enhancement of synaptic transmission induced by β-AR activation [161]. Thus, it will be interesting to see whether β-AR modulation of LTP is altered in AKAP and MAGUK mutant mice, as would be expected if AKAPs and MAGUKs are essential components of β-AR signaling complexes at excitatory synapses.

Importantly, recent evidence suggests that the composition of these receptor signaling complexes is not static but instead can be dynamically altered in an activity-dependent manner. For example, NMDA receptor activation rapidly redistributes AKAP 79/150 away from dendritic spines in hippocampal neurons [162,163]; this is associated with a decrease in synaptic levels of PKA RII subunits and a decrease in GluR1 phosphorylation at S845 [163]. The molecular basis for this effect is still unclear, although some evidence suggests that it is dependent on activation of PP2B and involves alterations in spine actin dynamics [162,163]. In any event, translocation of AKAPs and PKA away from dendritic spines following NMDA receptor activation could significantly affect the ability of β-AR activation to facilitate LTP induction. Indeed, prior activation of NMDA receptors induces a long-lasting and robust inhibition of the ability of β-AR activation to increase GluR1 phosphorylation at S845 in the hippocampal CA1 region [117,118]. Prior NMDA receptor activation also strongly inhibits increases in GluR1 phosphorylation at S845 induced by directly activating adenylate cyclase with forskolin [118]. This suggests that NMDA receptor-dependent changes in β-AR signaling are likely due to downstream components of the signaling pathway (such as AKAP and PKA localization) rather than a direct effect on β-ARs. If true, NMDA receptor activation may also disrupt other aspects of β-AR signaling that may be involved in enhancing LTP induction, such as modulation of Kv4.2 and SK3 type potassium channels. Thus, β-AR modulation of LTP may act like a modulatory switch – strongly facilitating the induction of LTP at naïve synapses but having no effect on plasticity at synapses where prior patterns of synaptic activity produced sufficient NMDA receptor activation to activate PP2B. Although the physiological significance of this phenomenon is unclear, it may act as a mechanism for protecting the storage of information encoded by decreases in synaptic strength induced by NMDA receptor-dependent LTD from erasure by the robust LTP-enhancing effects of β-AR activation.

It is clear that release of noradrenaline and subsequent β-AR activation can facilitate the storage of information that may not normally be encoded or retained. Such a mechanism could explain the increased clarity and strength of memories formed during times of intense emotions when noradrenaline release is increased [164]. Additionally, because memory enhancement is a key goal of many cognitive rehabilitation programs, the finding that β-AR activation can gate the dependence of synaptic plasticity on PKA, which is a key requirement for making new long-term memories [165], may provide novel insights on potential molecular drug targets for reducing memory deficits resulting from neurodegenerative diseases.