IκB Kinase/Nuclear Factor κB-Dependent Insulin-Like Growth Factor 2 (Igf2) Expression Regulates Synapse Formation and Spine Maturation via Igf2 Receptor Signaling

Schmeißer, Michael J.; Baumann, Bernd; Johannsen, Svenja; Vindedal, Gry Fluge; Jensen, Vidar R.; Hvalby, Øivind; Sprengel, Rolf; Seither, Jochen; Maqbool, Ayesha; Magnutzki, Alexander; Lattke, Michael; Oswald, Franz; Boeckers, Tobias M.; Wirth, Thomas

doi:10.1523/jneurosci.0111-12.2012

Cited by 122 publications

(115 citation statements)

References 70 publications

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“…Recent evidence suggests that IkK acts directly on other pathways, such as insulin and neurotrophic signaling cascades, to alter dendritic spines and neuronal function (Lee et al, 2007;Nakamori et al, 2006;Schmeisser et al, 2012). Schmeisser et al (2012) demonstrate that inhibition of IkK, via conditional expression of an IkKdn allele or knockout of IkK specifically in excitatory neurons, prevents synapse formation and maintenance in a manner that is dependent upon Igf2 signaling. Along similar lines, phosphorylation of TSC1 by IkK activates the mTOR pathway, which is known to be involved in spine plasticity, and mediates the rapid antidepressants effects of ketamine.…”

Section: Discussionmentioning

confidence: 93%

Effects of Inhibitor of κB Kinase Activity in the Nucleus Accumbens on Emotional Behavior

Christoffel

Golden

Heshmati

et al. 2012

Neuropsychopharmacol

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Inhibitor of kB kinase (IkK) has historically been studied in the context of immune response and inflammation, but recent evidence demonstrates that IkK activity is necessary and sufficient for regulation of neuronal function. Chronic social defeat stress of mice increases IkK activity in the nucleus accumbens (NAc) and this increase is strongly correlated to depression-like behaviors. Inhibition of IkK signaling results in a reversal of chronic social defeat stress-induced social avoidance behavior. Here, we more completely define the role of IkK in anxiety and depressive-like behaviors. Mice underwent stereotaxic microinjection of a herpes simplex virus expressing either green fluorescent protein, a constitutively active form of IkK (IkKca), or a dominant negative form of IkK into the NAc. Of all three experimental groups, only mice expressing IkKca show a behavioral phenotype. Expression of IkKca results in a decrease in the time spent in the nonperiphery zones of an open field arena and increased time spent immobile during a forced swim test. No baseline differences in sucrose preference were observed, but following the acute swim stress we noted a marked reduction in sucrose preference. To determine whether IkK activity alters responses to other acute stressors, we examined behavior and spine morphology in mice undergoing an acute social defeat stress. We found that IkKca enhanced social avoidance behavior and promoted thin spine formation. These data show that IkK in NAc is a critical regulator of both depressive-and anxiety-like states and may do so by promoting the formation of immature excitatory synapses.

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Section: Discussionmentioning

confidence: 93%

Effects of Inhibitor of κB Kinase Activity in the Nucleus Accumbens on Emotional Behavior

Christoffel

Golden

Heshmati

et al. 2012

Neuropsychopharmacol

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“…IGF2, like IGF1 and insulin, may also be beneficial in rescuing cognitive impairments in diseases, as it can promote synapse formation and spine maturation in the mouse brain (Schmeisser et al 2012), and perhaps through the IGF1receptor (IGF1R), may affect neurogenesis and consequently contribute to hippocampaldependent spatial learning and memory (Bracko et al 2012;Ouchi et al 2013). Like IGF1 and insulin, the expression of IGF2 and IGF2 receptor (IGF2R) have been found altered in the brain AD patients (Kar et al 2006) and IGF2 ameliorates AD-related deficits in an AD mouse model (Mellott et al 2014).…”

Section: Discussionmentioning

confidence: 99%

The effect of insulin and insulin-like growth factors on hippocampus- and amygdala-dependent long-term memory formation

2014

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Recent work has reported that the insulin-like growth factor 2 (IGF2) promotes memory enhancement. Furthermore, impaired insulin or IGF1 functions have been suggested to play a role in the pathogenesis of neurodegeneration and cognitive impairments, hence implicating the insulin/IGF system as an important target for cognitive enhancement and/or the development of novel treatments against cognitive disorders. Here, we tested the effect of intracerebral injections of IGF1, IGF2, or insulin on memory consolidation and persistence in rats. We found that a bilateral injection of insulin into the dorsal hippocampus transiently enhances hippocampal-dependent memory and an injection of IGF1 has no effect. None of the three peptides injected into the amygdala affected memories critically engaging this region. Together with previous data on IGF2, these results indicate that IGF2 produces the most potent and persistent effect as a memory enhancer on hippocampal-dependent memories. We suggest that the memory-enhancing effects of insulin and IGF2 are likely mediated by distinct mechanisms.

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“…An associated reduction of MAPK activity in Igf1R/InsR CaMKII-cre compared with Igf1R/InsR fl/fl mice, however, was restricted to the ACx and could not be observed in the Hi. Therefore, it seems likely that IGF2 signaling uses regionally different modes of action using both the IGF1R/INSR and IGF2R to activate MAPK in a context-dependent way (34,43,44,47). The significance of MAPK activity for the timing of memory formation in the hippocampus has been addressed already in a circadian context (15,17,41) and the disruption of clock genes leads to a memory impairment (48)(49)(50)(51).…”

Section: Discussionmentioning

confidence: 99%

Enhanced memory consolidation in mice lacking the circadian modulators Sharp1 and -2 caused by elevated Igf2 signaling in the cortex

Shahmoradi

Radyushkin

Rossner

2015

Proc. Natl. Acad. Sci. U.S.A.

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The bHLH transcription factors SHARP1 and SHARP2 are partially redundant modulators of the circadian system. SHARP1/DEC2 has been shown to control sleep length in humans and sleep architecture is also altered in double mutant mice (S1/2 −/− ). Because of the importance of sleep for memory consolidation, we investigated the role of SHARP1 and SHARP2 in cognitive processing. S1/2 −/− mice show enhanced cortex (Cx)-dependent remote fear memory formation as well as improved reversal learning, but do not display alterations in hippocampus (Hi)-dependent recent fear memory formation. SHARP1 and SHARP2 single null mutants do not display any cognitive phenotype supporting functional redundancy of both factors. Molecular and biochemical analyses revealed elevated insulin-related growth factor 2 (IGF2) signaling and increased phosphorylation of MAPK and S6 in the Cx but not the Hi of S1/2 −/− mice. No changes were detected in single mutants. Moreover, adenoassociated virus type 2-mediated IGF2 overexpression in the anterior cingulate cortex enhanced remote fear memory formation and the analysis of forebrain-specific double null mutants of the Insulin and IGF1 receptors revealed their essential function for memory formation. Impaired fear memory formation in aged S1/2 −/− mice indicates that elevated IGF2 signaling in the long term, however, has a negative impact on cognitive processing. In summary, we conclude that the bHLH transcription factors SHARP1 and SHARP2 are involved in cognitive processing by controlling Igf2 expression and associated signaling cascades. Our analyses provide evidence that the control of sleep and memory consolidation may share common molecular mechanisms.cortex | memory consolidation | insulin-like signaling | aging | MAPK signaling T he hippocampus (Hi) and anterior cortex (ACx) have been associated with different aspects of cognitive processes controlling, for example, recent and remote long-term fear memory formation, respectively (1). Current concepts suggest that longterm fear memory consolidation involves a gradual transfer of memory traces from hippocampal networks into stable cortical modules integrated by the anterior cingulate cortex (ACC) (2). Long-term memory consolidation is considered a highly dynamic process involving different cortical areas and is thought to be shaped already during encoding, storage, but also reconsolidation processes (3, 4). The gradual transfer of memory traces from the Hi to cortical structures is thought to be dependent on different aspects of sleep (5) such as the sleep-dependent memory replay between the Hi and the cortex (6). Thus, the controls of sleep and memory consolidation appear to be interconnected processes. It is well known that many aspects of sleep-wakerelated behavior are controlled by clock genes and emerging evidence suggests an involvement of the circadian system in cognitive processes (7). Several signaling pathways have been studied in the context of hippocampal learning (8-14), among those, the circadian timing of mitogen-activated prot...

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IκB Kinase/Nuclear Factor κB-Dependent Insulin-Like Growth Factor 2 (Igf2) Expression Regulates Synapse Formation and Spine Maturation via Igf2 Receptor Signaling

Cited by 122 publications

References 70 publications

Effects of Inhibitor of κB Kinase Activity in the Nucleus Accumbens on Emotional Behavior

Effects of Inhibitor of κB Kinase Activity in the Nucleus Accumbens on Emotional Behavior

The effect of insulin and insulin-like growth factors on hippocampus- and amygdala-dependent long-term memory formation

Enhanced memory consolidation in mice lacking the circadian modulators Sharp1 and -2 caused by elevated Igf2 signaling in the cortex

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