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A critical role for IGF-II in memory consolidation and enhancement. Nature

Department of Neuroscience, Mount Sinai School of Medicine, New York, New York 10029, USA.
Nature (Impact Factor: 41.46). 01/2011; 469(7331):491-7. DOI: 10.1038/nature09667
Source: PubMed

ABSTRACT

We report that, in the rat, administering insulin-like growth factor II (IGF-II, also known as IGF2) significantly enhances memory retention and prevents forgetting. Inhibitory avoidance learning leads to an increase in hippocampal expression of IGF-II, which requires the transcription factor CCAAT enhancer binding protein β and is essential for memory consolidation. Furthermore, injections of recombinant IGF-II into the hippocampus after either training or memory retrieval significantly enhance memory retention and prevent forgetting. To be effective, IGF-II needs to be administered within a sensitive period of memory consolidation. IGF-II-dependent memory enhancement requires IGF-II receptors, new protein synthesis, the function of activity-regulated cytoskeletal-associated protein and glycogen-synthase kinase 3 (GSK3). Moreover, it correlates with a significant activation of synaptic GSK3β and increased expression of GluR1 (also known as GRIA1) α-amino-3-hydroxy-5-methyl-4-isoxasolepropionic acid receptor subunits. In hippocampal slices, IGF-II promotes IGF-II receptor-dependent, persistent long-term potentiation after weak synaptic stimulation. Thus, IGF-II may represent a novel target for cognitive enhancement therapies.

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Available from: Sarah Stern, Apr 11, 2014
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    • "We also conclude that the dominant maternal expression in adult brain,Because we have previously reported that inhibitory avoidance (IA) training in rats leads to an increase in Igf2 levels in the dHC at 20hr after training, which is required for memory con- solidation[16], we next determined if the learning-dependent Igf2 increase is selective to one allele. Allele specific qPCR analyses of adult F (dam) x BN (sire) and BN (dam) x F (sire) F1 rat brains collected 20 hrs after IA training detected a significant increase of Igf2 level in the dHC 20 hrs after training (Fig 4A), consistent withChen et al. (2011). This increase derived proportionally from both alleles without significantly changing the ratio of maternal to paternal Igf2 mRNA expression levels, which remained 91.1% maternal (Fig 4A). "
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    ABSTRACT: Insulin like growth factor 2 (Igf2) is known as a maternally imprinted gene involved in growth and development. Recently, Igf2 was found to also be regulated and required in the adult rat hippocampus for long-term memory formation, raising the question of its allelic regulation in adult brain regions following experience and in cognitive processes. We show that, in adult rats, Igf2 is abundantly expressed in brain regions involved in cognitive functions, like hippocampus and prefrontal cortex, compared to the peripheral tissues. In contrast to its maternal imprinting in peripheral tissues, Igf2 is mainly expressed from the maternal allele in these brain regions. The training-dependent increase in Igf2 expression derives proportionally from both parental alleles, and, hence, is mostly maternal. Thus, Igf2 parental expression in the adult rat brain does not follow the imprinting rules found in peripheral tissues, suggesting differential expression regulation and functions of imprinted genes in the brain.
    Full-text · Article · Oct 2015 · PLoS ONE
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    • "There are several lines of evidence for resistance to IR/IGF1R signaling in AD neurons [8, 11, 14–16] whereas there are few data in terms of IGF2R actions in AD. However, in an experimental study by Chen et al. [18], IGF2R signaling was of major importance for memory consolidation [18]. In the human AD brain, IGF-II expression was reduced [21], and the expression of IGF-II and IGF2R as well as IGF2R binding decreased with advancing disease [14] [15]. "
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    ABSTRACT: Background: Insulin-like growth factor-II (IGF-II) is important for brain development. Although IGF-II is abundant also in adult life, little is known of the role of IGF-II in Alzheimer's disease (AD). Objective and methods: This was a cross-sectional study of 60 consecutive patients under primary evaluation of cognitive impairment and 20 healthy controls. The patients had AD dementia or mild cognitive impairment (MCI) diagnosed with AD dementia upon follow-up (n = 32), stable MCI (SMCI, n = 13), or other dementias (n = 15). IGF-II, IGF-binding protein-1 (IGFBP-1), and IGFBP-2 were analyzed in serum and cerebrospinal fluid (CSF). Results: Levels of IGF-II, IGFBP-1, and IGFBP-2 were similar in all groups in the total study population. Gender-specific analyses showed that in men (n = 40), CSF IGF-II level was higher in AD compared to SMCI and controls (p < 0.01 and p < 0.05, respectively). Furthermore, CSF IGFBP-2 level was increased in AD men versus SMCI men (p < 0.01) and tended to be increased versus control men (p = 0.09). There were no between-group differences in women (n = 40). In the total study population (n = 80) as well as in men (n = 40), CSF levels of IGF-II and IGFBP-2 correlated positively with CSF levels of the AD biomarkers total-tau and phosphorylated tau protein. Conclusion: In men, but not women, in the early stages of AD, CSF IGF-II level was elevated, and CSF IGFBP-2 level tended to be increased, compared to healthy controls.
    Full-text · Article · Sep 2015 · Journal of Alzheimer's disease: JAD
    • "Alberini and colleagues reported that hippocampal or systemic injection of recombinant IGF2 enhances memory retention and prevents forgetting (Chen et al., 2011; Stern et al., 2014b), and another group has also suggested that the hippocampal IGF2 pathway regulates the extinction of fear memory (Agis- Balboa et al., 2011). Chen et al. (2011)suggested that endogenous hippocampal IGF2 has a role in memory consolidation during a limited time window that lasts less than 4 days. However, it remains unclear whether exogenous IGF2 regulates the memory trace or whether such effects are active until several weeks. "
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    ABSTRACT: Memory consolidation is an important process for the formation of long-term memory. We have previously reported that mature brain-derived neurotrophic factor enhances memory consolidation within 9h after initial learning. Recent studies suggest that insulin-like growth factor 2 (IGF2) significantly enhances memory consolidation and prevents forgetting. Thus, we hypothesized that IGF2 exerts its activity on cognitive performance in a time-dependent manner as observed in our previous study. In the one-trial step-through inhibitory avoidance task, we demonstrate that a bilateral injection of IGF2 into the dorsal hippocampus 6 or 9h after training significantly enhanced the step-through latencies compared with the vehicle-treated controls in the retention trial, which was conducted 24h after the acquisition trial. However, 12h post-training, IGF2 injection did not increase the step-through latencies. Intriguingly, in the retention trial at 21 days after the training, hippocampal IGF2 injection 6, 9 or 12h after the acquisition trial significantly increased the step-through latencies compared with the vehicle-treated controls. IGF2 administration at 9h and 12h after the acquisition trial significantly increased discrimination index and exploration time on the novel-located object in the test trial at 24h and 21 days, respectively, after the acquisition trial in the novel location recognition task. In addition, IGF2-induced an increase in the step-through latencies in the retention trial 24h or 21 days, respectively, after the initial learning was completely abolished by co-injected anti-IGF2 receptor antibody. These results suggest that IGF2 enhances memory consolidation within 9h after initial learning, and increased IGF2 within the 12h after the acquisition trial, which represents a delayed consolidation phase, is also critical for memory persistence. Copyright © 2015. Published by Elsevier B.V.
    No preview · Article · Jul 2015 · Brain research
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