Jeffrey Greenwood, Pauline Curtis, Barbara Logan, Wickliffe Abraham and Mike Dragunow
How long-term memories are formed in the brain is one of the principal targets of contemporary neuroscience research. This work is important from a fundamental perspective, because memory is a vital component of virtually all cognitive activity. It is also important from a clinical perspective since the early and most dramatic symptoms of Alzheimer's disease (AD) are an impairment of memory formation. Diseases such as AD can provide clues about which neurotransmitters and intracellular signalling pathways are involved in human memory formation. In this chapter, the importance of muscarinic cholinergic signalling in memory formation and AD will be discussed. The classical immediate early genes (IEGs) implicated in memory formation, and the signalling cascades which may regulate their activity will then be described. Finally, our recent work on the potential involvement of stress response immediate early genes in memory formation will be presented.
The brain neurotransmitter acetylcholine has been shown to be critical for long-term memory storage38'54 and drugs which activate muscarinic acetylcholine receptors improve memory by activating a system that is critical in memory formation (see refs. 36 and 46, and also Pepeu and Giovannini in this book for review). The best predictor of the cognitive decline in AD is the loss of acetylcholine markers in the brain reflecting death or atrophy of acetylcholine-producing neurons in the basal forebrain,8,10 indicating that the memory loss in AD may be due to a reduction in acetylcholine signalling through muscarinic receptors on post-synaptic neurons. Cholinesterase inhibitors (which elevate acetylcholine in brain, such as tacrine) delay the progression of AD,31 and their effects may be due to a combination of direct cognitive actions and enhanced acetylcholine signalling through postsynaptic Mi muscarinic receptors, the latter having been shown to activate secretion of soluble amyloid precursor proteins23 and reduce tau phosphorylation.25,52 Although postsynaptic Mi muscarinic receptors are not lost in AD brain,37 there is a large impairment in signalling via the phosphoinositide (PI) system,40 and this impairment in AD brain membranes is mimicked by application of amyloid-P-peptide, a peptide found in AD plaques and implicated strongly in AD causation,44 to cultured neurons.41 There is also a relationship between apolipoprotein E4 (APOE4), which is a risk factor for developing AD, and cholinergic systems such that the APOE4 allele is associated with greater loss of cholinergic markers and a reduced responsiveness to cholinergic agonists in AD.50 APOE-deficient mice show a cholinergic impairment and memory formation problems that can be ameliorated by M1 agonists,24 and an impairment in muscarinic agonist-induced PI hydrolysis.14 Thus, Mi muscarinic receptor signalling is severely impaired in AD brain and this is likely to contribute to the memory formation problems seen in AD patients, as well as for the poor efficacy of M1 agonists in AD. Glutamate is also fundamental to memory formation and memory consolidation, and readers are referred to many excellent reviews on this topic in the literature (e.g., see ref. 48 and also Riedel et al in this book).
Long-term changes in neuronal phenotype are required for the formation of long-term memories in the brain.43 The discovery many years ago that the c-fos IEG, which codes for a transcription factor, was induced in neurons after various types of physiological and pathological stimulation generated great excitement in the neuroscience community because it provided the first indication that the neuronal genome was responsive to activation of membrane-bound receptors.34 In particular, researchers interested in memory consolidation wondered whether c-fos might provide the link to the neuronal genome underlying the formation of long-term memory. Thus, neurotransmitters might cause permanent changes in neuronal phenotype by accessing the neuronal genome through induction of transcription factors (coded for by IEGs) such as c-Fos.20,26,47 While this turned out not to be the case for c-fos,16 other IEGs have emerged as better candidates. For example, it was shown that both glutamate, acting via N-methyl-D-aspartate (NMDA) receptors, and acetylcholine, acting via muscarinic receptors, induce the Krox 24 IEG product and transcription factor in neurons. 13,33,34,51,57,59The induction of Krox 24 (but not c-Fos) via NMDA receptors predicts the permanence of synaptic changes in the long-term potentiation (LTP) model of memory storage,2,5,51 implying that Krox 24 may be involved in inducing genes responsible for long-term memory stor-age.9,15,17,18,49,61 These data have been well reviewed over the past few years.3,18,61 Until recently, the link between krox 24 expression and LTP maintenance have been purely correlational. However, Jones et al39 recently provided direct evidence for this relationship. They showed that the late, protein synthesis-dependent phase of LTP is absent in mice with a targeted disruption of krox 24. Furthermore, these mice exhibited long-term, but not short-term, memory deficits. Thus, Krox 24 appears to be a transcription factor that is vital for memory consolidation.
Muscarinic receptor agonists enhance memory storage through a delayed action,46 and muscarinic antagonists, which cause amnesia in humans,1 block neuronal krox 24 expression,33 suggesting that Krox 24 is an intermediate signalling molecule linking muscarinic receptor activation to memory-related gene expression. However, other transcription factors are also likely to act in concert with Krox 24. For example, phosphorylation of the transcription factor cyclic AMP response element binding protein (CREB) is also strongly implicated in long-term memory storage.53 We recently discovered a novel signalling pathway linking muscarinic receptor agonists to CREB phosphorylation (maximal at 5-10 min) followed by Krox 24 induction (maximal 1 h) in human neuroblastoma cells.19,27 Exactly how muscarinic receptor agonists activate CREB phosphorylation is unclear but the mechanism could involve one of several signalling cascades. Interestingly, we have discovered that Krox 24 induction downstream of muscarinic receptor activation is dependent on p42/44 mitogen activated protein (MAP) ki-nase activity, as it is blocked by the MEK inhibitor U0126, whereas CREB phosphorylation is unaffected by MAP kinase blockade.27 Thus, the activation of muscarinic receptors leads to activation of both CREB and Krox 24, but these pathways appear to be parallel rather than sequential, with one (Krox 24) being dependent upon activation of the MAP kinase cascade while the other (CREB) is not. At present the functional implications of this are unclear. However, the ability of muscarinic agonists to activate two transcription factors, both of which play important roles in memory consolidation, might account for the importance of cholinergic signal transduction in learning and memory.
IEGs and Their Relation to Stress
In addition to classical IEGs such as krox 24 being involved in memory and LTP, we have recently discovered that transcription factors normally associated more with stress responses are also activated by LTP-inducing stimulation. In particular, we have been interested in how transcription factors such as Activating Transcription Factor 3 (ATF3) might be involved in LTP and hence memory processes. This interest stems in part from studies showing that c-Jun N-terminal kinase (JNK) activity, which is associated with some forms of cellular stress and apoptosis (see refs. 44 and 63, as well as 62), is also activated in the CNS by environmental stimulation.65 Furthermore, one JNK target, c-Jun, is switched on in neurons during LTP5 ATF3 (also called LRF-1 in rat, LRG-21, CRG-5 and TI-241 in mouse) is a member of the ATF/CREB family of bZIP transcription factors but cannot be detected basally in neurons.21,22,30,32,35 ATF3 has the characteristics of an IEG, with its induction being independent of protein synthesis.22 The rapid induction ofATF3 by a number of physiological stress signals has led to its general designation as a stress response gene.28,29 In the nervous system, for example, induction of ATF3 has been observed following peripheral nerve axotomy55,58 and pentylenetetrazole-induced seizure activity.12 This induction may be linked to Ca2+ influx, as ATF3 is also induced in SH-SY5Y neuroblastoma cells by calcium ionophore treatment.7 In addition, there is evidence that induction of ATF3 is downstream of JNK activation.11,29 The induction of ATF3 following seizures and the possible link to Ca2+ flux and JNK activation prompted us to ask if ATF3 is induced as a consequence of nonpathological synaptic activity.
i .• . •
i r 50 nm
Figure 2. Time course for ATF3 induction in dentate granule cells following 50 T HFS. Brains were removed at the indicated times after the 50 T HFS protocol and coronal brain sections were immunostained for ATF3. Control and tetanised hemispheres are indicated.
We conducted experiments in freely moving adult rats which had bilateral chronically-indwelling stimulating and recording electrodes implanted suitable for recording perforant path-evoked field potentials in the dentate gyrus.5 High-frequency stimulation (HFS, 400 Hz) was delivered to the perforant path of one hemisphere, with the contralateral hemisphere used as a nontetanised control. Brains were removed and frozen at defined times post-tetanisation (as described in detail previously in ref. 5), and 16 ^m frozen coronal brain sections cut through the dorsal hippocampus were fixed and immunostained with antibodies to ATF3 (Santa Cruz sc-188) or Krox 24 (Santa Cruz sc-189). Antibody binding was visualised by peroxidase/ 3,3'-diaminobenzidine (DAB) staining.63
In these studies we observed ATF3 induction following HFS of the perforant path input to the dentate gyrus. A robust tetanisation protocol of 50 trains (50 T), delivered as described by Abraham et al,5 which reliably induces LTP lasting weeks in the dentate gyrus,6 resulted in ATF3 induction 2 h post-tetanisation in the dentate granule cell layer on the tetanised side, but not on the control side (Fig. 1A). This response coincided with the induction of Krox 24, which was strongly induced throughout the dentate granule cell layer of the tetanised hemisphere (Fig. 1B). However, the ATF3 expression appeared confined to the nuclei of a proportion of the granule cells (Fig. 1C) unlike the more general Krox 24 immunostaining. In sections that contained the path of electrode insertion, some ATF3 staining was evident in cells immediately surrounding the needle track for both hemispheres of the brain (results not shown), a result consistent with ATF3 being induced by tissue damage.29
50 T CPP
t f • • t
*' ' *
Figure 3. ATF3 induction in dentate granule cells varies with tetanisation protocol and is NMDA receptor dependent. Brains were removed 2 h after the indicated HFS protocols, and coronal brain sections were immunostained for ATF3. The NMDA receptor antagonist CPP (10 mg/kg) was injected i.p. 2 h prior to HFS (bottom panel). Control and tetanised hemispheres are indicated.
The time course of ATF3 expression in dentate granule cells was determined following completion of the 50 T HFS protocol (Fig. 2). No ATF3 immunostaining was present in dentate granule cells 10 min after completion of the 50 T protocol (4/4 animals). At 2 h post-tetanisation, 6/6 animals showed ATF3 immunostaining in a proportion of the dentate granule cells on the tetanised side. ATF3 expression was still present at 4 h post-tetanisation (6/8 animals), and was declining but still visible at 8 h post-tetanisation (2/3 animals). This time course of ATF3 expression is quite similar to that described for Krox 24, which shows a peak at 1-2 h and has returned to baseline by 8 h post-tetanisation.51
To determine whether the induction of ATF3 in dentate granule cells by HFS bore any relationship to LTP induction and stability, we compared ATF3 immunostaining at 2 h post-tetanisation following a range of tetanisation protocols (Fig. 3). As described above, the robust 50 T protocol reliably induced ATF3 expression (6/6 animals). Pretreatment with the NMDA receptor antagonist 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) completely blocked ATF3 induction 2 h following the 50 T protocol (Fig. 3, 4/4 animals), showing that the induction of ATF3, like LTP, is dependent on NMDA receptor activation. A 20 train protocol (20 T), which induces robust LTP that is however less stable than that induced by 50 T5,64 resulted in low but detectable ATF3 expression (2/3 animals). A spaced protocol of 20 trains administered in 4 sets of 5 trains with 10 min between each (4x5 T) did not result in ATF3 induction (4/4 animals). All of these protocols typically show substantial initial LTP,4,5 indicating a poor correlation between LTP induction and ATF3 expression. This is also the case for Krox 24 induction, which shows a better correlation with LTP persistence than with the initial level of LTP.51 However, the 4x5 T protocol typically produces more stable LTP than the condensed burst-type 20 T protocol,4 which suggests that the strength of ATF3 induction is more closely related to the intensity of the HFS protocol than the stability of the resulting LTP
Overall, we found from these experiments that protocols with fewer or less sustained bouts of tetanisation were less effective at inducing ATF3 expression. These results suggest that components of a stress response may be initiated in dentate granule cells following robust HFS protocols, possibly as a result of a large amplitude Ca2+ influx via NMDA receptors. Details of the signalling molecules involved in ATF3 induction in this system are not clear at present. However, we have preliminary evidence that the related transcription factor ATF2 is phospho-rylated at Thr69/71 10 min after 50 T HFS (data not shown). Because the ATF3 promoter can be activated by ATF2/c-Jun heterodimers,42 this result suggests that the induction of ATF3 after HFS may be mediated by activation of ATF2 and c-Jun. We have previously shown that ATF2 is phosphorylated in neurons undergoing apoptosis.63 Furthermore, we hypothesised that Jun/ATF2 heterodimers cause apoptosis.60 Clearly, dentate granule cells do not undergo apoptosis after LTP stimulation, but activation of stress-associated signalling cassettes in these neurons suggests some stress-related LTP processes. Whether these responses influence the characteristics of induced LTP is not clear at present.
In conclusion, recent data39 provide support for the hypothesis, proposed many years previ-ously3 that the IEG krox 24 codes for a transcription factor (Krox 24) that links short-term neuronal events to long-term events required for consolidation of long-term memory storage. Although many other transcription factors are also induced by LTP stimulation, their role in memory processes is not as well defined. However, studies showing that LTP stimulation elicits not only changes in transcription factors classically associated with plasticity (e.g., Krox 24) but also in transcription factors linked historically to stress responses (e.g., ATF3, ATF2, c-Jun) increase the range of molecules associated with this model of memory formation. Whether this is because LTP represents a stress-response paradigm rather than a pure model of memory formation, or whether ATF3, ATF2 and c-Jun have multiple functions in addition to their presumed role in cell stress, is presently unclear.
Studies of IEG involvement in LTP and memory processes have revealed important signal transduction pathways that control the formation of long-term memories in the brain. Many challenges and opportunities lie ahead, including identifying the late-response genes activated by transcription factors such as Krox 24 (e.g., synapsin so that the molecular events involved in encoding the engram can be fully defined. The clinical implications of this work have yet to be fully realised but the hope is that drugs and/or gene therapy approaches, based upon these memory signalling cassettes, will one day provide a rational and effective approach to treating memory disorders such as AD.
Supported by grants from the Marsden Fund and the Health Research Council of New Zealand.
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