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. An understanding of the mechanisms of memory enhancement is vital for broadening our knowledge of memory processes, as well as for potential clinical applications. Yet very little is known about it. Experiments in rats now show that the administration of insulin-like growth factor II (IGF-II), a protein typically implicated in somatic tissue growth and repair, significantly enhances memory retention, promotes the memory proxy known as long-term potentiation and prevents forgetting. IGF-II acts by initiating a network of signalling cascades that can lead to synaptic potentiation and are most effective within a short time frame immediately following learning. IGF-II is therefore a potential target for modulating cognitive enhancement. After learning, memories are strengthened through a process called 'consolidation', which requires new gene and protein expression, rendering new information less vulnerable to disruption. Several transcription factor families are involved in this process, but many of the relevant downstream targets are unknown. Here, IGF-II, a protein typically implicated in somatic tissue growth and repair, is identified as an essential factor in memory retention. IGF-II initiates its own network of signalling cascades that can lead to synaptic potentiation and are most effective within a short time frame immediately after learning. Thus, IGF-II represents an endogenous target for potentially modulating cognitive enhancement.

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

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