Episodic memories formed during the first postnatal period are rapidly forgotten, a phenomenon known as infantile amnesia. In spite of this memory loss, early experiences influence adult behavior, raising the question of which mechanisms underlie infantile memories and amnesia. Here we show that in rats an experience learned during the infantile amnesia period is stored as a latent memory trace for a long time; indeed, a later reminder reinstates a robust, context-specific and long-lasting memory. The formation and storage of this latent memory requires the hippocampus, follows a sharp temporal boundary, and occurs through mechanisms typical of developmental critical periods, including brain-derived-neurotrophic-factor (BDNF)- and metabotropic-glutamate-receptor-5 (mGluR5)-dependent expression switch of the N-methyl-D-aspartate receptor subunits 2B-2A. BDNF or mGlur5 activation after training rescues the infantile amnesia. Thus, early episodic memories are not lost, but remain stored long-term. These data suggest that the hippocampus undergoes a developmental critical period to become functionally competent.

Little is known about the temporal progression and regulation of the mechanisms underlying memory consolidation. Brain-derivedneurotrophic-factor (BDNF) has been shown to mediate the maintenance of memory consolidation, but the mechanisms of this regulation remain unclear. Using inhibitory avoidance (IA) in rats, here we show that a hippocampal BDNF-positive autoregulatory feedback loop via CCAAT-enhancer binding protein ␤ (C/EBP␤) is necessary to mediate memory consolidation. At training, a very rapid, learninginduced requirement of BDNF accompanied by rapid de novo translation controls the induction of a persistent activation of cAMPresponse element binding-protein (CREB) and C/EBP␤ expression. The latter, in turn, controls an increase in expression of bdnf exon IV transcripts and BDNF protein, both of which are necessary and, together with the initial BDNF requirement, mediate memory consolidation. The autoregulatory loop terminates by 48 h after training with decreased C/EBP␤ and pCREB and increased methyl-CpG binding protein-2, histone-deacetylase-2, and switch-independent-3a binding at the bdnf exon IV promoter.

Infantile amnesia, the inability of adults to recollect early episodic memories, is associated with the rapid forgetting that occurs in childhood. It has been suggested that infantile amnesia is due to the underdevelopment of the infant brain, which would preclude memory consolidation, or to deficits in memory retrieval. Although early memories are inaccessible to adults, early-life events, such as neglect or aversive experiences, can greatly impact adult behavior and may predispose individuals to various psychopathologies. It remains unclear how a brain that rapidly forgets, or is not yet able to form long-term memories, can exert such a long-lasting and important influence. Here, with a particular focus on the hippocampal memory system, we review the literature and discuss new evidence obtained in rats that illuminates the paradox of infantile amnesia. We propose that infantile amnesia reflects a developmental critical period during which the learning system is learning how to learn and remember.The long-lasting influence of episodic infantile experiences and the paradox of infantile amnesia How do we develop our abilities to learn and remember facts, people, things, relationships, and places? These memories define our identities; they store autobiographical episodes that can be consciously declared, and are therefore termed declarative memories. Declarative memories include both the experience of specific things, people, and events of a given time and place (episodic memories), and general knowledge about the world (semantic memories). They are also known as explicit memories because they require conscious recollection (Graf and Schacter, 1985). These are the memories that are lost in Alzheimer's disease or aging-related memory impairment. Parallels of these memories exist in nonhuman animals and include contextual, spatial, and episodic memories (Ergorul and Eichenbaum, 2004). Collectively, such memories store information about "who, what, when and where," and are therefore termed "wwww" memories. In both humans and nonhuman mammals, wwww memories are processed by the hippocampus-dependent (or medial temporal lobe-dependent) learning and memory system (Eichenbaum, 2006; Squire and Wixted, 2011;Lavenex and Banta Lavenex, 2013;Albani et al., 2014).A large body of clinical and behavioral evidence has demonstrated the critical importance of infantile episodic experiences for brain function throughout life. However, little is known about the biological mechanisms underlying the development of the hippocampus-dependent learning and memory system. Many studies have shown that hippocampus-dependent memories (also referred to as hippocampal memories) are severely compromised by challenges occurring early in life. These challenges may be either psychological (e.g., trauma, neglect, or deprivation of social experience) or biological (e.g., the impact of genetic mutations on development). All of these events can predispose individuals to psychopathologies, such as post-traumatic stress disorder, borderline personality ...

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There is a significant overlap between brain areas with Zn(2+) and Cu(2+) pathological dys-homeostasis and those in which the nerve growth factor (NGF) performs its biological role. The protein NGF is necessary for the development and maintenance of the sympathetic and sensory nervous systems. Its flexible N-terminal region has been shown to be a critical domain for TrkA receptor binding and activation. Computational analyses show that Zn(2+) and Cu(2+) form pentacoordinate complexes involving both the His4 and His8 residues of the N-terminal domain of one monomeric unit and the His84 and Asp105 residues of the other monomeric unit of the NGF active dimer. To date, neither experimental data on the coordination features have been reported, nor has one of the hypotheses according to which Zn(2+) and Cu(2+) may have different binding environments or the Ser1 α-amino group could be involved in coordination been supported. The peptide fragment, encompassing the 1-14 sequence of the human NGF amino-terminal domain (NGF(1-14)), blocked at the C terminus, was synthesised and its Cu(2+) and Zn(2+) complexes characterized by means of potentiometric and spectroscopic (UV/Vis, CD, NMR, and EPR) techniques. The N-terminus-acetylated form of NGF(1-14) was also investigated to evaluate the involvement of the Ser1 α-amino group in metal-ion coordination. Our results demonstrate that the amino group is the first anchoring site for Cu(2+) and is involved in Zn(2+) coordination at physiological pH. Finally, a synergic proliferative activity of both NGF(1-14) and the whole protein on SHSY5Y neuroblastoma cell line was found after treatment in the presence of Cu(2+). This effect was not observed after treatment with the N-acetylated peptide fragment, demonstrating a functional involvement of the N-terminal amino group in metal binding and peptide activity.