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

Abstract

We report that, in the rat, administering insulin-like growth factor II (IGF-II) 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 glycogensynthase kinase 3 (GSK3). Moreover, it correlates with a significant activation of synaptic GSK3β and expression of GluR1 a-amino-3-hydroxy-5-methyl-4-isoxasoleproprionic 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.

Placental programming of anxiety in adulthood revealed by Igf2-null models

“…Acute manipulations of Igf2 in adults have been shown to regulate neurogenesis in brain and have an impact on fear-related behaviour [42][43][44] ; however, these effects are, a priori, difficult to reconcile with the selective pattern of effects seen here, as Igf2 expression is intact in Igf2-P0 KO adult mice. Other factors such as differences between the models arising from the lack of imprinting of Igf2 in choroid plexus and leptomeninges of the brain can also be discounted, because this would affect the Igf2-total KO mice (leading to a 50% reduction of Igf2 expression in these tissues), but not the Igf2-P0 KO mice.…”

FoxO6 regulates memory consolidation and synaptic function

“…The capacity to retain transient waves of insulin/IGF/PI3K signaling activity (leading to FoxO activity oscillations) may be needed during memory retention and retrieval (Lin et al 2001;Opazo et al 2003;Chen et al 2005;Horwood et al 2006). Indeed, recent studies have also shown that injection of an IGF family member, IGF2, into the hippocampus after training enhanced memory (Chen et al 2011) and that injection of IGF2 after extinction trials facilitated extinction of memory (Agis-Balboa et al 2011). Finally, it is also possible that the positive effects on memory retention of insulin/IGF are mediated by other targets of the insulin/IGF pathway (i.e., mTOR, GSK3, etc.)…”

“…Finally, it is also possible that the positive effects on memory retention of insulin/IGF are mediated by other targets of the insulin/IGF pathway (i.e., mTOR, GSK3, etc.) (Chen et al 2011).…”

“…Activating the insulin/IGF pathway-which is known to inhibit FoxO factors-is important for memory retention and synaptogenesis (O'Kusky et al 2000;Aleman and Torres-Aleman 2009;Chen et al 2011). On the other hand, reducing the insulin/IGF pathwaywhich is known to activate FoxO factors-is important for extending longevity and preventing symptoms of Alzheimer's disease (Cohen et al 2009;Freude et al 2009;Killick et al 2009).…”

“…At the organismal level, the deletion of FoxO1 or FoxO3 results in reduced anxiety-and depression-like behaviors, respectively (Polter et al 2009). Interestingly, the insulin/ IGF pathway, which regulates FoxO transcription factors, has been found to impact learning and memory in physiological or pathological conditions such as Alzheimer's disease (Cohen et al 2009;Freude et al 2009;Killick et al 2009;Chen et al 2011). However, the importance and mode of action of the hippocampal-enriched FoxO6 in cognitive behavior are not known.…”