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Role of Protein Synthesis and DNA Methylation in the Consolidation and Maintenance of Long-Term Memory in Aplysia Authors:Kaycey

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Role of Protein Synthesis and DNA Methylation in the Consolidation and Maintenance of Long-Term Memory in Aplysia Authors:Kaycey 1 Role of Protein Synthesis and DNA Methylation in the Consolidation and 2 Maintenance of Long-Term Memory in Aplysia 3 Authors:KayceyPearce1, Diancai Cai1,Adam C. Roberts1,and David L. Glanzman1,2,3‡ 4 Affiliations: 5 1Department of Integrative Biology and Physiology, UCLA, Los Angeles, CA 90095. 6 2Department of Neurobiology, David Geffen School of Medicine at UCLA, Los 7 Angeles, CA 90095. 8 3Integrative Center for Learning and Memory, Brain Research Institute, UCLA, Los 9 Angeles, CA 90095. 10 11 ‡Correspondence should be addressed to: [email protected] 12 13 Key words: 14 Long-term memory, memory consolidation, retrograde amnesia, epigenetics, DNMT, 15 DNA methyltransferase, 16 17 Major research organism: 18 Aplysia californica 19 20 21 22 Abstract 23 Previously, we reported that long-term memory (LTM) in Aplysiacan be reinstated by 24 truncated (partial) training following its disruption by reconsolidation blockade and 25 inhibition of PKM (Chen et al., 2014).Here, we report thatLTM can be induced by partial 26 training after disruption of original consolidation by protein synthesis inhibition (PSI) 27 begun shortly after training. But when PSI occurs during training, partial training cannot 28 subsequently establish LTM. Furthermore, we find that inhibition of DNA 29 methyltransferase (DNMT), whether during training or shortly afterwards, blocks 30 consolidation of LTM and prevents its subsequent induction by truncated training; 31 moreover, later inhibition of DNMT eliminates consolidated LTM. Thus, the 32 consolidation of LTM depends on two functionally distinct phases of protein synthesis: 33 an early phase that appears to prime LTM; and a later phase whose successful completion 34 is necessary for the normal expression of LTM. Both the consolidation and maintenance 35 of LTM depend on DNA methylation. 36 37 Impact Statement 38 Behavioral and synaptic investigations of long-term memory in Aplysia reveal novel 39 functional distinctions among protein synthesis during training, protein synthesis shortly 40 after training and DNA methylation with respect to memory consolidation and 41 maintenance. 42 43 44 45 Introduction 46 Since the pioneering work of the Flexners(Flexner et al 1963), Agranoff(Agranoff & 47 Klinger 1964) and their colleagues, it has been widely accepted that memory 48 consolidation—the process by which a labile, short-term memory trace is transformed 49 into a stable,long-term trace (Lechner et al 1999, Müller & Pilzecker 1900)—requires 50 protein synthesis (Davis & Squire 1984, Goelet et al 1986, Hernandez & Abel 2008). 51 Moreover, the protein synthesis underlying memory consolidation has been observed to 52 exhibit a temporal gradient: inhibition of protein synthesis during or shortly after 53 trainingappears to be maximally disruptive of memory consolidation; significantly less 54 amnesia is caused by protein synthesis inhibition (PSI) that commences approximately an 55 hour or more after training (Davis & Squire 1984). 56 In general, there has been littleevidence for a functional distinction with respect to 57 memory consolidation between protein synthesis that occurs during training—hereafter 58 “early” protein synthesis—and protein synthesis that occurs within the first hour or so 59 after the end of training—hereafter “late” protein synthesis.Thus, studies have classically 60 observed significant disruptive effects on the consolidation of long-term memory (LTM) 61 whether a protein synthesis inhibitor is applied either immediately prior to, or 62 immediately after, training (e.g., Agranoff et al 1966, Barondes & Cohen 1968, Flexner 63 & Flexner 1968). Consequently, both early and late protein synthesis are commonly 64 regarded as participating in a more-or-lessunitary consolidative process. In particular, 65 protein synthesis is believed to mediate critical late events in memory consolidation, 66 including late gene transcription via the synthesis of transcription factors, such as the 67 CCAAT/enhancer-binding protein (C/EBP), and the consequent synthesis of proteins 68 involved in the construction of new synaptic connections (Bailey et al 2015, Kandel et al 69 2014). 70 One mechanism increasingly implicated in the consolidation of LTM is the 71 epigenetic process of DNA methylation (Levenson et al 2006, Maddox et al 2014, Miller 72 et al 2008, Monsey et al 2011, Oliveira 2016, Rajasethupathy et al 2012). However, the 73 relationship between protein synthesis and DNA methylation in memory consolidation is 74 unclear. Mechanistically, is protein synthesis upstream or downstream of DNA 75 methylation during consolidation? DNA methylation is usually associated with gene 76 silencing. If DNA methylation is required for the synthesis of necessary consolidative 77 proteins, this would imply that a prerequisite for this synthesis is the silencing of one or 78 more repressor genes. On the other hand, it is possible that activation of DNA 79 methyltransferase (DNMT), the family of enzymes that catalyze the transfer of a methyl 80 group to DNA, during memory consolidation itself depends on protein synthesis. Of 81 course, these two possibilities are not mutually exclusive. 82 Here, we have examined the potentially distinctive roles of early and late protein 83 synthesis in the consolidation of the LTM for behavioral sensitization in Aplysia. In 84 addition, we have tested the effect on memory consolidation of both early and late 85 inhibition of DNA methylation. We find that LTM can be induced by partial training, 86 which is insufficient to induce LTM in naïve (untrained) animals, after the disruption of 87 LTM by late, but not early, administration of a protein synthesis inhibitor. By contrast, 88 both early and late inhibition of DNMT block LTM consolidation as indicated by the 89 preclusion of subsequent memory induction by partial training. These results point to a 90 functional distinction between early and late protein synthesis in memory consolidation, 91 and suggest a potential role for early protein synthesis in DNA methylation. Finally, we 92 show that inhibition of DNMT disrupts not only the consolidation, but also the 93 persistence, of LTM; thus, the maintenance of consolidated LTM requiresongoing DNA 94 methylation. 95 96 Results 97 LTM can be induced by truncated sensitization training following amnesia 98 produced by posttraining PSI 99 Animals were given training that induced long-term sensitization (LTS) of the siphon 100 withdrawal reflex (SWR); this training (hereafter 5X training) consisted of five bouts of 101 tail shocks spaced 20 min apart (Cai et al 2011, Cai et al 2012, Chen et al 2014) (Figure 102 1). Control animals received no training. Then, ~ 15 min (range = 10-20 min) after 103 training, trained animals received an intrahemocoelic injection of anisomycin, a protein 104 synthesis inhibitor,or vehicle solution. Control animals received an injection of vehicle 105 solution at the equivalent experimental time. At 24 hafter training the duration of the 106 SWR was tested in all the animals (24-hposttest), after which two of the groups—the 107 control group (Control-Veh-3XTrained) and a group that had received the long-term 108 training plus the posttraining injection of anisomycin (5XTrained-Aniso-3XTrained) 109 were given additional sensitization training, which consisted of three bouts of tail shocks 110 spaced 20 min apart. Previously, we found that this training (hereafter 3X training), 111 which isinsufficient to induce LTM in naïve animals,can successfully reinstate LTM 112 following its disruption by inhibition of PKM Apl III—the Aplysia homolog of PKMζ 113 (Bougie et al 2012, Bougie et al 2009)—or memory reconsolidation blockade (Chen et al 114 2014). All the groups, including the two that received the 5X training but not the 3X 115 training (5XTrained-Veh and 5XTrained-Aniso groups),were given another test at 48 116 hafter training or at the equivalent experimental time (48 hposttest). 117 The group given 5X training followed by vehicle injection (5XTrained-Veh 118 group) exhibited significant sensitization at 24 hafter training compared with the two 119 groups that received the 5X training followed by anisomycin injection (5XTrained-Aniso 120 and 5XTrained-Aniso-3XTrained groups), and with the control group (Control-Aniso- 121 3XTrained). The subsequent 3X training produced LTS in the 5XTrained-Aniso- 122 3XTrainedgroup, as shown by the results for the 48-hposttest.(Notice that the 3X training 123 did not induce LTS in animals that did not receive prior 5X training.)Thus, although 124 posttraining PSIproduced complete amnesia for sensitization at 24 h, it did not preclude 125 the subsequent establishment of LTS by partial training. 126 Previous work (Montarolo et al 1986)examined the effect of PSI at various times 127 after training on serotonin (5HT)-dependent, long-term facilitation (LTF) of the 128 sensorimotor synapse in dissociated cell culture, an in vitro homolog of LTS in 129 Aplysia(Kandel 2001). This work demonstrated that LTF, tested at 24 hafter training, 130 was disrupted by anisomycin applied during a 3-h period that extended from 1 hbefore 131 the onset of spaced 5HT trainingthrough 0.5 hafter training (Montarolo et al 1986).(The 132 5HT training lasted 1.5 h.)By contrast, a 3-h period of anisomycin treatment beginning at 133 either 0.5 hor 4 hafter the end of 5HT training did not block LTF. Considering our 134 behavioral results (above), we wished to determine whether exposure to a protein 135 synthesis inhibitor immediately after 5HT
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