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.
1. Aarsland D, Larsen JP, Reinvang I et al. Effects of cholinergic blockade on language in healthy young women. Implications for the cholinergic hypothesis in dementia of the Alzheimer type. Brain 1994; 117:1377-1384.
2. Abraham WC, Christie BR, Logan B et al. Immediate early gene expression associated with the persistence of heterosynaptic long-term depression in the hippocampus. Proc Natl Acad Sci USA 1994; 91:10049-10053.
3. Abraham WC, Dragunow M, Tate WP. The role of immediate early genes in the stabilization of long-term potentiation. Mol Neurobiol 1991; 5:297-314.
4. Abraham WC, Logan B, Greenwood JM et al. Induction and experience-dependent consolidation of stable long-term potentiation lasting months in the hippocampus. J Neurosci 2002; 22:9626-9634.
5. Abraham WC, Mason SE, Demmer J et al. Correlations between immediate early gene induction and the persistence of long-term potentiation. Neurosci 1993; 56:717-727.
6. Abraham WC, Mason-Parker SE, Williams J et al. Analysis of the decremental nature of LTP in the dentate gyrus. Mol Brain Res 1995; 30:367-372.
7. Adler EM, Fink JS. Calcium regulation of vasoactive intestinal polypeptide mRNA abundance in SH-SY5Y human neuroblastoma cells. J Neurochem 1993; 61:727-737.
8. Bartus RT, Dean III RL, Beer B et al. The cholinergic hypothesis of geriatric memory dysfunction. Science 1982; 217:408-414.
9. Beckmann AM, Wilce PA. Egr transcription factors in the nervous system. Neurochem Int 1997; 31:477-516.
10. Bierer LM, Haroutunian V, Gabriel S et al. Neurochemical correlates of dementia severity in Alzheimer's disease: Relative importance of the cholinergic deficits. J Neurochem 1995; 64:749-760.
11. Cai Y, Zhang C, Nawa T et al. Homocysteine-responsive ATF3 gene expression in human vascular endothelial cells: Activation of c-Jun NH2-terminal kinase and promoter response element. Blood 2000; 96:2140-2148.
12. Chen BP, Wolfgang CD, Hai T. Analysis of ATF3, a transcription factor induced by physiological stresses and modulated by gadd153/Chop10. Mol Cell Biol 1996; 16:1157-1168.
13. Cole AJ, Saffen DW, Baraban JM et al. Rapid increase of an immediate early gene messenger RNA in hippocampal neurons by synaptic NMDA receptor activation. Nature 1989; 340:474-476.
14. De Sarno P, Jope RS. Phosphoinositide hydrolysis activated by muscarinic or glutamatergic, but not adrenergic, receptors is impaired in ApoE-deficient mice and by hydrogen peroxide and peroxynitrite. Exp Neurol 1998; 152:123-128.
15. Desjardins S, Mayo W, Vallee M et al. Effect of aging on the basal expression of c-Fos, c-Jun, and Egr-1 proteins in the hippocampus. Neurobiol Aging 1997; 18:37-44.
16. Douglas RM, Dragunow M, Robertson HA. High-frequency discharge of dentate granule cells, but not long-term potentiation, induces c-fos protein. Brain Res 1988; 464:259-262.
17. Dragunow M. Differential expression of immediate-early genes during synaptic plasticity, seizures and brain injury suggests specific functions for these molecules in brain neurons. In: Tolle TR, Zieglgansberger W, eds. Immediate-early genes in the CNS: More than just activity markers. Springer, New York: 1994:33-50.
18. Dragunow M. A role for immediate-early transcription factors in learning and memory. Behav Genet 1996; 26:293-299.
19. Dragunow M, Henderson C. An in vitro model system to investigate muscarinic receptor-mediated induction of the CREB and Krox 24 memory-related transcription factors. In: Keystone Symposium on Molecular Mechanisms of Alzheimer's Disease. Taos, New Mexico:1999:50.
20. Dragunow M, Robertson HA. Kindling stimulation induces c-fos protein(s) in granule cells of the rat dentate gyrus. Nature 1987; 329:441-442.
21. Drysdale BE, Howard DL, Johnson RJ. Identification of a lipopolysaccharide inducible transcription factor in murine macrophages. Mol Immunol 1996; 33:989-998.
22. Farber JM. A collection of mRNA species that are inducible in the RAW 264.7 mouse macrophage cell line by gamma interferon and other agents. Mol Cell Biol 1992; 12:1535-1545.
23. Farber SA, Nitsch RM, Schulz JG et al. Regulated secretion of beta-amyloid precursor protein in rat brain. J Neurosci 1995; 15:7442-7451.
24. Fisher A, Brandeis R, Chapman S et al. M1 muscarinic agonist treatment reverses cognitive and cholinergic impairments of apolipoprotein E-deficient mice. J Neurochem 1998; 70:1991-1997.
25. Genis I, Fisher A, Michaelson DM. Site-specific dephosphorylation of tau of apolipoprotein E-deficient and control mice by M1 muscarinic agonist treatment. J Neurochem 1999; 72:206-213.
26. Greenberg ME, Ziff EB, Greene LA. Stimulation of neuronal acetylcholine receptors induces rapid gene transcription. Science 1986; 234:80-83.
27. Greenwood JM, Dragunow M. Muscarinic receptor-mediated phosphorylation of cyclic AMP response element binding protein in human neuroblastoma cells. J Neurochem 2002; 82:389-397.
28. Hai T, Hartman MG. The molecular biology and nomenclature of the activating transcription factor/cAMP responsive element binding family of transcription factors: Activating transcription factor proteins and homeostasis. Gene 2001; 273:1-11.
29. Hai T, Wolfgang CD, Marsee DK et al. ATF3 and stress responses. Gene Expr 1999; 7:321-335.
30. Hai TW, Liu F, Coukos WJ et al. Transcription factor ATF cDNA clones: An extensive family of leucine zipper proteins able to selectively form DNA-binding heterodimers. Genes Dev 1989; 3:2083-2090.
31. Holford NH, Peace KE. Methodologic aspects of a population pharmacodynamic model for cognitive effects in Alzheimer patients treated with tacrine. Proc Natl Acad Sci USA 1992; 89:11466-11470.
32. Hsu JC, Laz T, Mohn KL et al. Identification of LRF-1, a leucine-zipper protein that is rapidly and highly induced in regenerating liver. Proc Natl Acad Sci USA 1991; 88:3511-3515.
33. Hughes P, Dragunow M. Activation of pirenzepine-sensitive muscarinic receptors induces a specific pattern of immediate-early gene expression in rat brain neurons. Mol Brain Res 1994; 24:166-178.
34. Hughes P, Dragunow M. Induction of immediate-early genes and the control of neurotransmitter-regulated gene expression within the nervous system. Pharmacol Rev 1995; 47:133-178.
36. Izquierdo I, da Cunha C, Rosat R et al. Neurotransmitter receptors involved in post-training memory processing by the amygdala, medial septum, and hippocampus of the rat. Behav Neural Biol 1992; 58:16-26.
37. Jansen KL, Faull RL, Dragunow M et al. Alzheimer's disease: Changes in hippocampal N-methyl-D-aspartate, quisqualate, neurotensin, adenosine, benzodiazepine, serotonin and opioid receptors—an autoradiographic study. Neurosci 1990; 39:613-627.
38. Jerusalinsky D, Kornisiuk E, Izquierdo I. Cholinergic neurotransmission and synaptic plasticity concerning memory processing. Neurochem Res 1997; 22:507-515.
39. Jones MW, Errington ML, French PJ et al. A requirement for the immediate early gene Zif268 in the expression of late LTP and long-term memories. Nature Neurosci 2001; 4:289-296.
40. Jope RS, Song L, Powers RE. Cholinergic activation of phosphoinositide signaling is impaired in Alzheimer's disease brain. Neurobiol Aging 1997; 18:111-120.
41. Kelly JF, Furukawa K, Barger SW et al. Amyloid beta-peptide disrupts carbachol-induced muscarinic cholinergic signal transduction in cortical neurons. Proc Natl Acad Sci USA 1996; 93:6753-6758.
42. Liang G, Wolfgang CD, Chen BP et al. ATF3 gene. Genomic organization, promoter, and regulation. J Biol Chem 1996; 271:1695-1701.
43. Matthies H. In search of cellular mechanisms of memory. Prog Neurobiol 1989; 32:277-349.
44. Mattson MP. Cellular actions of beta-amyloid precursor protein and its soluble and fibrillogenic derivatives. Physiol Rev 1997; 77:1081-1132.
45. Mielke K, Herdegen T. JNK and p38 stress kinases—degenerative effectors of signal-transduction-cascades in the nervous system. Prog Neurobiol 2000; 61:45-60.
46. Mondadori C, Hengerer B, Ducret T et al. Delayed emergence of effects of memory-enhancing drugs: Implications for the dynamics of long-term memory. Proc Natl Acad Sci USA 1994; 91:2041-2045.
47. Morgan JI, Cohen DR, Hempstead JL et al. Mapping patterns of c-fos expression in the central nervous system after seizure. Science 1987; 237:192-197.
48. Newcomer JW, Krystal JH. NMDA receptor regulation of memory and behavior in humans. Hippocampus 2001; 11:529-542.
49. O'Donovan KJ, Tourtellotte WG, Millbrandt J et al. The EGR family of transcription-regulatory factors: Progress at the interface of molecular and systems neuroscience. Trends Neurosci 1999; 22:167-173.
50. Poirier J, Delisle MC, Quirion R et al. Apolipoprotein E4 allele as a predictor of cholinergic deficits and treatment outcome in Alzheimer disease. Proc Natl Acad Sci USA 1995; 92:12260-12264.
51. Richardson CL, Tate WP, Mason SE et al. Correlation between the induction of an immediate early gene, zif/268, and long-term potentiation in the dentate gyrus. Brain Res 1992; 580:147-154.
52. Sadot E, Gurwitz D, Barg J et al. Activation of m1 muscarinic acetylcholine receptor regulates tau phosphorylation in transfected PC12 cells. J Neurochem 1996; 66:877-880.
53. Silva AJ, Kogan JH, Frankland PW et al. CREB and memory. Annu Rev Neurosci 1998; 21:127-148.
54. Sirvio J. Strategies that support declining cholinergic neurotransmission in Alzheimer's disease patients. Gerontol 1999; 45:3-14.
55. Takeda M, Kato H, Takamiya A et al. Injury-specific expression of activating transcription factor-3 in retinal ganglion cells and its colocalized expression with phosphorylated c-Jun. Invest Ophthalmol Vis Sci 2000; 41:2412-2421.
56. Thiel G, Schoch S, Petersohn D. Regulation of synapsin I gene expression by the zinc finger transcription factor zif268/egr-1. J Biol Chem 1994; 269:15294-15301.
57. Tsiokas L, Watson M. Differential in vivo induction of immediate early genes by oxotremorine in the central nervous system of long- and short-sleep mice. Mol Pharmacol 1995; 47:272-282.
58. Tsujino H, Kondo E, Fukuoka T et al. Activating transcription factor 3 (ATF3) induction by axotomy in sensory and motoneurons: A novel neuronal marker of nerve injury. Mol Cell Neurosci 2000; 15:170-182.
59. von der Kammer H, Mayhaus M, Albrecht C et al. Muscarinic acetylcholine receptors activate expression of the EGR gene family of transcription factors. J Biol Chem 1998; 273:14538-14544.
60. Walton MR, Dragunow M et al. Is CREB a key to neuronal survival? Trends Neurosci 2000; 23:48-53.
61. Walton M, Henderson C, Mason-Parker S et al. Immediate early gene transcription and synaptic modulation. J Neurosci Res 1999; 58:96-106.
62. Walton M, MacGibbon G, Young D et al. Do c-Jun, c-Fos, and amyloid precursor protein play a role in neuronal death or survival? J Neurosci Res 1998; 53:330-342.
63. Walton M, Woodgate AM, Sirimanne E et al. ATF-2 phosphorylation in apoptotic neuronal death. Mol Brain Res 1998; 63:198-204.
64. Williams J, Dragunow M, Lawlor P et al. Krox20 may play a key role in the stabilization of long-term potentiation. Mol Brain Res 1995; 28:87-93.
65. Xu X, Raber J, Yang D et al. Dynamic regulation of c-Jun N-terminal kinase activity in mouse brain by environmental stimuli. Proc Natl Acad Sci USA 1997; 94:12655-12660.
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